Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis
Open accessPublished version of a preprint
Abstract
The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer's disease and has been implicated as a suppressor of melanoma progression. The APOE germline genotype predicts human melanoma outcomes, with APOE4 and APOE2 allele carriers exhibiting prolonged and reduced survival, respectively, relative to APOE3 homozygotes. While the APOE4 variant was recently shown to suppress melanoma progression by enhancing antitumor immunity, further work is needed to fully characterize the melanoma cell-intrinsic effects of APOE variants on cancer progression. Using a genetically engineered mouse model, we showed that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner. The low-density lipoprotein receptor-related protein 1 (LRP1) receptor mediated the cell-intrinsic effects of APOE variants on melanoma progression. Protein synthesis was a tumor cell-intrinsic process differentially modulated by APOE variants, with APOE2 promoting translation via LRP1. These findings reveal a gain-of-function role for the APOE2 variant in melanoma progression, which may aid in predicting melanoma patient outcomes and understanding the protective effect of APOE2 in Alzheimer's disease. Significance: APOE germline variants impact melanoma progression through disparate mechanisms, such as the protein synthesis–promoting function of the APOE2 variant, indicating that germline genetic variants are causal contributors to metastatic outcomes.
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Written from the paper’s full text.
TL;DR
Using human APOE knock-in melanoma GEMMs and human TCGA data, this study shows that APOE2 promotes melanoma growth, metastasis, and protein synthesis via LRP1, opposite to APOE4. It identifies mRNA translation as an APOE variant-dependent, tumor cell-intrinsic process and supports a gain-of-function role for APOE2 in melanoma progression.
Key findings
- In BPC/APOE GEMMs, melanoma progression followed APOE2 > APOE3 > APOE4: median survival was 42.5 days for BPC/APOE2, 53.5 days for BPC/APOE3, and 59.5 days for BPC/APOE4; BPC/APOE2 mice also had substantially more lung metastatic foci than BPC/APOE4 mice.
- RNA-Seq/GSEA showed translation as the most upregulated pathway in BPC/APOE2 tumors versus BPC/APOE4 tumors, and SUnSET confirmed higher puromycin incorporation in APOE2 tumors and in APOE2-overexpressing B16F10 cells; translation pathways were also top-upregulated in APOE2 metastases relative to APOE3.
- LRP1 mediated these effects: CRISPR/Cas9 deletion of melanoma Lrp1 abrogated the metastatic burden difference between APOE2 and APOE4 mice, and BPC/APOE2/LRP1Δ versus BPC/APOE4/LRP1Δ mice showed no significant difference in tumor latency, growth rate, or endpoint tumor volume, with equalized puromycin incorporation.
- In TCGA-SKCM, primary tumors from APOE2 carrier patients exhibited upregulation of translation pathways relative to APOE4 carriers and APOE3 homozygotes, and this was maintained in metastatic tumors.
Methods
- The authors crossed the BrafV600E/+;Pten−/−;Tyr::CreER melanoma GEMM with human APOE2, APOE3, or APOE4 knock-in mice, and further crossed BPC/APOE2 and BPC/APOE4 mice with Lrp1flox/flox mice to delete Lrp1 in melanocytes.
- Tumor initiation used topical or perinatal 4-hydroxytamoxifen; metastasis was assessed by lung pigmented foci, tail vein injection of B16F10-TR-shApoe cells, bioluminescence, histology, and flow-sorted metastatic cells.
- Protein synthesis was measured by SUnSET in vivo and in vitro; bulk RNA-Seq with GSEA was performed on BPC tumors, sorted lung metastases, and TCGA-SKCM data.
Limitations
- The paper states that the BPC GEMM is poorly immunogenic, which may preclude immune differences from developing by the day 49 time point, and that future studies are needed to elucidate the molecular mechanism downstream of the APOE2/LRP1 axis.
- The paper states that the worldwide APOE2 allele frequency is less than ten percent, limiting statistical power, which is why the authors turned to large public datasets such as TCGA-SKCM.
- Evident from the text: human evidence is correlative transcriptomic analysis of TCGA-SKCM rather than direct experimental manipulation, and in the GEMM, tumoral APOE expression was most prominent in the APOE2 background, a difference controlled in vitro but potentially confounding in vivo.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
39 of 45 cited sources checked · 27 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Genetic variation in APOE is a significant modulator of survival after melanoma development.
“We previously identified genetic variation in the secreted glycoprotein apolipoprotein E (APOE) as a significant modulator of survival after melanoma development (3).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Ostendorf, 2020, Common germline variants of the human APOE gene modulate melanoma progression and survival, Nat Med source
- Premisecitation
APOE4 suppresses tumor angiogenesis and endothelial recruitment by cancer cells.
“Moreover, APOE4 has been shown to suppress tumor angiogenesis and endothelial recruitment by cancer cells (3,4).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [3] Ostendorf, 2020, Common germline variants of the human APOE gene modulate melanoma progression and survival, Nat Med source
- cites [4] Pencheva, 2012, Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis, Cell source
The Results sections report that melanoma cell-secreted ApoE suppresses endothelial recruitment and that ApoE suppresses metastatic angiogenesis. The Discussion identifies the studied melanoma cell lines as homozygous for ApoE3 and discusses recombinant ApoE3; it does not establish these effects for APOE4. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
We previously found that the APOE receptor LRP1 mediates the cell-intrinsic effects of APOE on melanoma cells.
“We previously found that the APOE receptor LRP1 mediates the cell-intrinsic effects of APOE on melanoma cells (4).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] Pencheva, 2012, Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis, Cell source
- Interpretationcitation
This result is consistent with prior findings revealing that the APOE4 background confers potent anti-tumor immunity.
“This result is consistent with our prior findings revealing that the APOE4 background confers potent anti-tumor immunity (3).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Ostendorf, 2020, Common germline variants of the human APOE gene modulate melanoma progression and survival, Nat Med source
- Premisecitation
Both tumor-derived and stroma-derived APOE regulate melanoma metastatic capacity via extracellular action on tumoral APOE receptors.
“APOE protein is known to act extracellularly on tumoral APOE receptors, and both tumor-derived and stroma-derived APOE have been found to regulate melanoma metastatic capacity in this manner (4,5).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [4] Pencheva, 2012, Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis, Cell source
The Discussion reports that melanoma cell-secreted and systemic ApoE suppress metastatic progression, and the Results identify melanoma-cell LRP1 as a receptor mediating ApoE-dependent invasion and metastatic colonization (page unavailable). The paper does not identify systemic ApoE specifically as stroma-derived or establish that its effect on metastasis acts through tumoral receptors; it also reports an effect through endothelial LRP8. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [5] Pencheva, 2014, Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation, Cell source
- Findingcitation
mRNA translation is upregulated in the brains of APOE2 carriers relative to those of APOE3 homozygotes and APOE4 carriers, based on examination of previously published transcriptomic and proteomic Alzheimer's datasets.
“Supporting the idea that our findings may have broader disease implications, our examination of previously published transcriptomic and proteomic Alzheimer’s datasets revealed that mRNA translation is a pathway that is upregulated in the brains of APOE2 carriers relative to those of APOE3 homozygotes and APOE4 carriers (41,42).”
Quote in the paperNot a substantial claim2 of 2 sources checked - Interpretationown data
The APOE variants exert cell-intrinsic effects on melanoma that impact primary tumor growth and metastatic capacity in a BrafV600E-driven GEMM.
“We reveal that the APOE variants exert cell-intrinsic effects on melanoma that impact primary tumor growth and metastatic capacity in a BrafV600E-driven GEMM, a model that has provided numerous important insights into melanoma biology (12,38–40).”
Quote in the paperSubstantial claim3 of 4 sources checked- cites [12] Spranger, 2015, Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity, Nature source
- cites [38] Deuker, 2015, PI3'-kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma, Cancer Discov source
- cites [39] Maertens, 2013, Elucidating distinct roles for NF1 in melanomagenesis, Cancer Discov source
- cites [40] Xie, 2015, Atg7 overcomes senescence and promotes growth of BrafV600E-driven melanoma, Cancer Discov source
- Findingown data
Western blot confirmed tumoral APOE expression, which was most prominent in the APOE2 background.
“Western blot confirmed tumoral APOE expression, which was most prominent in the APOE2 background (Supplementary Fig. S1A).”
Quote in the paperSubstantial claim - Findingnone given
These effects were dependent on melanoma cell expression of LRP1, a receptor for APOE.
“These effects were dependent on melanoma cell expression of low-density lipoprotein receptor-related protein 1 (LRP1), a receptor for APOE.”
Quote in the paperSubstantial claim - Findingown data
There is no significant difference in CD8+ T cell infiltration between BPC/APOE2 and BPC/APOE4 tumors at the day 49 endpoint.
“Histological staining revealed no significant difference in CD8+ T cell infiltration between BPC/APOE2 and BPC/APOE4 tumors at the day 49 endpoint (Supplementary Figs. S1B and S1C).”
Quote in the paperSubstantial claim - Findingown data
Human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner.
“Using a genetically engineered mouse model, we showed that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner.”
- Also stated in: § Introduction · plain
“We found that genetically initiated melanoma growth and metastasis were regulated by APOE genotype in an APOE2>E3>E4 manner.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · plain
- Findingown data
Melanoma onset occurred with shortest latency in BPC/APOE2 mice, followed by BPC/APOE3 mice and then BPC/APOE4 mice.
“Melanoma onset occurred with shortest latency in BPC/APOE2 mice, followed by BPC/APOE3 mice and then BPC/APOE4 mice (Figs. 1B, 1C).”
Quote in the paperSubstantial claim - Findingown data
Tumor progression and metastasis between BPC/APOE4 and BPC/APOE4/LRP1Δ mice was unchanged.
“Tumor progression and metastasis between BPC/APOE4 and BPC/APOE4/LRP1Δ mice was unchanged (Supplementary Figs. S4E–G)”
Quote in the paperSubstantial claim - Findingown data
This difference was diminished compared to Lrp1 wild-type BPC/APOE2 and BPC/APOE4 mice.
“However, this difference was diminished compared to Lrp1 wild-type BPC/APOE2 and BPC/APOE4 mice (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
Protein translation upregulation in the APOE2 background relative to APOE4 was maintained in metastatic tumors.
“Protein translation upregulation in the APOE2 background relative to APOE4 was also maintained in metastatic tumors, suggesting that APOE2 promotes protein synthesis in the melanomas of APOE2 carriers throughout the metastatic cascade (Fig. 4C; Supplementary Table 3).”
Quote in the paperSubstantial claim - Findingown data
After CRISPR/Cas9-mediated deletion of melanoma Lrp1 via two independent guide RNAs, the difference in metastatic burden between APOE2 and APOE4 mice was abrogated.
“However, after CRISPR/Cas9-mediated deletion of melanoma Lrp1 via two independent guide RNAs (Supplementary Fig. S3A), the difference in metastatic burden between APOE2 and APOE4 mice was abrogated (Fig. 3B, Supplementary Fig. S3B).”
Quote in the paperSubstantial claim - Findingown data
BPC/APOE2 tumors displayed significant upregulation in all major steps of translation present in the Reactome gene set relative to BPC/APOE4 tumors.
“BPC/APOE2 tumors displayed significant upregulation in all major steps of translation present in the Reactome (29) gene set relative to BPC/APOE4 tumors (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data
BPC/APOE2 tumors exhibited significantly higher puromycin incorporation than BPC/APOE4 tumors.
“Consistent with our RNA-Seq results, BPC/APOE2 tumors exhibited significantly higher puromycin incorporation than BPC/APOE4 tumors, indicative of either a slower translation rate in the APOE4 background or enhanced translation rate in the APOE2 background (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
Additional protein synthesis-related pathways 'Ribosomal RNA processing' and 'Eukaryotic translation elongation' were among the top ten upregulated pathways.
“The additional protein synthesis-related pathways ‘Ribosomal RNA processing’ and ‘Eukaryotic translation elongation’ were also among the top ten upregulated pathways.”
Quote in the paperSubstantial claim - Findingown data
There was no significant difference in tumor latency between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ mice.
“In contrast to the differential effects of APOE variants observed in Lrp1 wild-type mice, there was no significant difference in tumor latency (Fig. 3C), tumor growth rate (Fig. 3D), or tumor volume at the experimental endpoint (Supplementary Fig. S4B) between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ mice.”
Quote in the paperSubstantial claim - Findingown data
In a separate survival experiment, there was a significant difference with BPC/APOE2/LRP1Δ mice exhibiting a median survival of 55 days compared to 63 days in BPC/APOE4/LRP1Δ mice.
“In a separate survival experiment, there was a significant difference with BPC/APOE2/LRP1Δ mice exhibiting a median survival of 55 days compared to 63 days in BPC/APOE4/LRP1Δ mice (Fig. 3E).”
Quote in the paperSubstantial claim - Findingown data
Translation-related processes again dominated the top ten upregulated pathways in APOE2 metastases relative to APOE3.
“Importantly, translation-related processes again dominated the top ten upregulated pathways in APOE2 metastases relative to APOE3 (Fig. 2G; Supplementary Table 2).”
Quote in the paperSubstantial claim - Findingown data
Primary tumors from APOE2 carrier patients exhibited upregulation of translation pathways relative to tumors from APOE4 carriers.
“Consistent with our findings in BPC/APOE2 and BPC/APOE4 mice, primary tumors from APOE2 carrier patients exhibited upregulation of translation pathways relative to tumors from APOE4 carriers (Fig. 4B; Supplementary Table 3).”
Quote in the paperSubstantial claim - Findingown data
Equalization of melanoma progression between BPC/APOE2 and BPC/APOE4 mice upon Lrp1 deletion was largely driven by decreased tumor growth and metastasis in the APOE2 background.
“Of note, equalization of melanoma progression between BPC/APOE2 and BPC/APOE4 mice upon Lrp1 deletion was largely driven by decreased tumor growth and metastasis in the APOE2 background.”
Quote in the paperSubstantial claim - Findingown data
The SUnSET assay showed equalization of puromycin incorporation between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ tumors upon Lrp1 deletion.
“The SUnSET assay was performed with day 35 BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ tumors and showed equalization of puromycin incorporation between the genotypes upon Lrp1 deletion (Fig. 3G).”
Quote in the paperSubstantial claim - Findingown data
APOE3 exhibited an intermediate phenotype in our GEMM studies.
“APOE3 served as an ideal isogenic control for determining whether APOE2 mediates translational enhancement because it exhibited an intermediate phenotype in our GEMM studies and is the most common APOE variant in the human population (7).”
Quote in the paperSubstantial claim - Findingown data
BPC/APOE2 mice exhibited substantially more lung metastatic foci compared to BPC/APOE4 mice.
“Pigmented foci were visible on the lungs of mice (Supplementary Fig. S1D), and BPC/APOE2 mice exhibited substantially more lung metastatic foci compared to BPC/APOE4 mice (Fig. 1G).”
Quote in the paperSubstantial claim - Findingown data
After tail vein injection, control B16F10 melanoma cells depleted of murine APOE metastasized to the lung more efficiently in syngeneic APOE2 knock-in mice relative to APOE4 mice.
“After tail vein injection, control B16F10 melanoma cells depleted of murine APOE metastasized to the lung more efficiently in syngeneic APOE2 knock-in mice relative to APOE4 mice (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
Pigmented foci were visible on the lungs of mice.
“Pigmented foci were visible on the lungs of mice (Supplementary Fig. S1D), and BPC/APOE2 mice exhibited substantially more lung metastatic foci compared to BPC/APOE4 mice (Fig. 1G).”
Quote in the paperSubstantial claim - Findingown data
No difference in puromycin incorporation between control, APOE3, and APOE4 cells.
“We observed no difference in puromycin incorporation between control, APOE3, and APOE4 cells, whereas APOE2 cells exhibited substantially increased puromycin signal (Figs. 2D and 2E).”
Quote in the paperSubstantial claim - Findingown data
GSEA revealed that translation was the most upregulated pathway in BPC/APOE2 tumors relative to BPC/APOE4 tumors.
“Gene set enrichment analysis (GSEA) (28) revealed that translation was the most upregulated pathway in BPC/APOE2 tumors relative to BPC/APOE4 tumors (Fig. 2A; Supplementary Table 1).”
Quote in the paperSubstantial claim - Findingown data
Immunofluorescence staining of BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ tumors at the mouse survival endpoint revealed enhanced CD8+ T cell infiltration into APOE4 tumors.
“Indeed, immunofluorescence staining of BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ tumors at the mouse survival endpoint revealed enhanced CD8+ T cell infiltration into APOE4 tumors (Supplementary Fig. S4C and S4D).”
Quote in the paperSubstantial claim - Findingown data
There was no significant difference in tumor growth rate between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ mice.
“In contrast to the differential effects of APOE variants observed in Lrp1 wild-type mice, there was no significant difference in tumor latency (Fig. 3C), tumor growth rate (Fig. 3D), or tumor volume at the experimental endpoint (Supplementary Fig. S4B) between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ mice.”
Quote in the paperSubstantial claim - Findingown data
There was no significant difference in tumor volume at the experimental endpoint between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ mice.
“In contrast to the differential effects of APOE variants observed in Lrp1 wild-type mice, there was no significant difference in tumor latency (Fig. 3C), tumor growth rate (Fig. 3D), or tumor volume at the experimental endpoint (Supplementary Fig. S4B) between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ mice.”
Quote in the paperSubstantial claim - Findingown data
There was no significant difference in lung metastasis between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ mice after neonatal 4-OHT administration.
“There was no significant difference in lung metastasis between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ mice after neonatal 4-OHT administration (Fig. 3F), consistent with melanoma cell-intrinsic effects of APOE dominating at the metastatic site.”
Quote in the paperSubstantial claim - Findingown data
APOE2 cells exhibited substantially increased puromycin signal.
“We observed no difference in puromycin incorporation between control, APOE3, and APOE4 cells, whereas APOE2 cells exhibited substantially increased puromycin signal (Figs. 2D and 2E).”
Quote in the paperSubstantial claim - Findingown data
APOE2 mice had a significantly higher fraction of GFP+ tumor cells within their dissociated lungs relative to APOE3 mice.
“APOE2 mice had a significantly higher fraction of GFP+ tumor cells within their dissociated lungs relative to APOE3 mice, indicative of higher metastatic burden (Supplementary Fig. S2D).”
Quote in the paperSubstantial claim - Findingown data
Translation pathways were the top upregulated processes in APOE2 carrier primary tumors compared to APOE3 homozygotes.
“Also consistent with the notion that APOE2 is an active promoter of protein synthesis, translation pathways were also the top upregulated processes in APOE2 carrier primary tumors compared to APOE3 homozygotes (Supplementary Figs. S5A and 5B; Supplementary Table 3).”
Quote in the paperSubstantial claim - Findingown data
There is no difference in LRP1 expression among the APOE2, APOE3, and APOE4 backgrounds in vivo or in vitro.
“We observed no difference in LRP1 expression among the APOE2, APOE3, and APOE4 backgrounds in vivo or in vitro (Supplementary Figs. S4H and S4I).”
Quote in the paperSubstantial claim - Findingown data
Deletion of Lrp1 abrogated differences in tumor growth, metastasis, and protein synthesis between APOE2 and APOE4 mice.
“Deletion of Lrp1 abrogated differences in tumor growth, metastasis, and protein synthesis between APOE2 and APOE4 mice.”
Quote in the paperSubstantial claim - Interpretationreasoning
The result suggests a mechanism distinct from anti-tumor immunity by which APOE variants can differentially modulate tumor growth in the BPC GEMM.
“Nevertheless, this result suggests a mechanism distinct from anti-tumor immunity by which APOE variants can differentially modulate tumor growth in the BPC GEMM.”
Quote in the paperSubstantial claim - Interpretationown data
Our findings uncover a new, surprising role of APOE and its genetic variants as differential modulators of mRNA translation in melanoma.
“In sum, our findings uncover a new, surprising role of APOE and its genetic variants as differential modulators of mRNA translation in melanoma.”
Quote in the paperSubstantial claim - Study design and conductown data
Under normal growth conditions there was no difference in proliferation rates among the cell lines.
“Additionally, under normal growth conditions there was no difference in proliferation rates among the cell lines, thus enabling us to control for the tumor growth differences observed in vivo (Supplementary Fig. S2C).”
Quote in the paperSubstantial claim - Study design and conductown data
APOE was expressed at equivalent levels amongst the APOE2, APOE3, and APOE4 cell lines.
“Importantly, APOE was expressed at equivalent levels amongst the APOE2, APOE3, and APOE4 cell lines, thus controlling for differences in APOE expression levels present in the genetic model (Supplementary Fig. S2B).”
Quote in the paperSubstantial claim - Interpretationown data
LRP1 is required for the enhanced protein synthesis effect mediated by APOE2 in melanoma.
“Moreover, LRP1 is required for the enhanced protein synthesis effect mediated by APOE2 in melanoma.”
Quote in the paperSubstantial claim - Interpretationown data
LRP1 mediates the cell-intrinsic effects of the APOE variants.
“Having determined that LRP1 mediates the cell-intrinsic effects of the APOE variants”
Quote in the paperSubstantial claim - Interpretationown data
The lack of difference in lung metastasis is consistent with melanoma cell-intrinsic effects of APOE dominating at the metastatic site.
“There was no significant difference in lung metastasis between BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ mice after neonatal 4-OHT administration (Fig. 3F), consistent with melanoma cell-intrinsic effects of APOE dominating at the metastatic site.”
Quote in the paperSubstantial claim - Interpretationown data
APOE2 is acting in a gain-of-function manner to promote melanoma progression in this context.
“again supporting the notion that APOE2 is acting in a gain-of-function manner to promote melanoma progression in this context.”
Quote in the paperSubstantial claim - Premisecitation
The worldwide allele frequency of APOE2 is less than ten percent.
“Given that the worldwide allele frequency of APOE2 is less than ten percent (35), which limits statistical power, we turned to large public datasets.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Singh, 2006, APOE distribution in world populations with new data from India and the UK, Ann Hum Biol source
- Study design and conductown data
Immunofluorescence staining of BPC/APOE2/LRP1Δ and BPC/APOE4/LRP1Δ tumors showed substantial loss of LRP1 signal compared to Lrp1 wild-type tumors, confirming successful Cre-mediated deletion.
“Immunofluorescence staining of BPC/APOE2;Lrp1flox/flox (BPC/APOE2/LRP1Δ) and BPC/APOE4;Lrp1flox/flox (BPC/APOE4/LRP1Δ) tumors showed substantial loss of LRP1 signal compared to Lrp1 wild-type tumors, confirming successful Cre-mediated deletion (Supplementary Fig. S4A).”
Quote in the paperSubstantial claim - Interpretationcitation
APOE2 and APOE4 carry out opposing functions in melanoma.
“We propose a model in which APOE2 and APOE4 carry out opposing functions in melanoma, with APOE2 promoting growth, metastasis, and protein translation via the LRP1 receptor and APOE4 repressing progression via its suppression of multiple cancer phenotypes including invasion, angiogenesis and immune evasion, as demonstrated in previous work (3) (Fig. 4D).”
Quote in the paperSubstantial claim - Interpretationown data
These results revealed a potent impact of hereditary genetics on tumor growth and metastatic colony formation in an autochthonous model of melanoma progression.
“These results in the APOE variant GEMM revealed a potent impact of hereditary genetics on tumor growth and metastatic colony formation in an autochthonous model of melanoma progression.”
Quote in the paperSubstantial claim - Interpretationown data
APOE2 promotes protein synthesis in the melanomas of APOE2 carriers throughout the metastatic cascade.
“Protein translation upregulation in the APOE2 background relative to APOE4 was also maintained in metastatic tumors, suggesting that APOE2 promotes protein synthesis in the melanomas of APOE2 carriers throughout the metastatic cascade (Fig. 4C; Supplementary Table 3).”
Quote in the paperSubstantial claim - Interpretationown data
Common germline variation in a human gene-APOE-differentially regulates tumor and metastatic progression, as evidenced from a genetically initiated model.
“We moreover provide evidence from a genetically initiated model that common germline variation in a human gene —APOE— differentially regulates tumor and metastatic progression.”
Quote in the paperSubstantial claim - Interpretationown data
These findings reveal that the effects of APOE variants on melanoma metastatic capacity are mediated via the APOE receptor LRP1.
“These findings reveal that the effects of APOE variants on melanoma metastatic capacity are mediated via the APOE receptor LRP1.”
Quote in the paperSubstantial claim - Interpretationown data
The APOE receptor LRP1 is a required mediator of the cell-intrinsic effect of APOE2 on melanoma progression at the early primary tumor and metastasis stages.
“These findings reveal that the APOE receptor LRP1 is a required mediator of the cell-intrinsic effect of APOE2 on melanoma progression at the early primary tumor and metastasis stages.”
Quote in the paperSubstantial claim - Interpretationreasoning
BPC/APOE4/LRP1Δ mice are likely provided an advantage over BPC/APOE2/LRP1Δ mice in a survival experiment that allows more time for anti-tumor immunity to develop in this poorly immunogenic genetic model.
“BPC/APOE4/LRP1Δ mice are likely provided an advantage over BPC/APOE2/LRP1Δ mice in a survival experiment that allows more time for anti-tumor immunity to develop in this poorly immunogenic genetic model.”
Quote in the paperSubstantial claim - Interpretationreasoning
Germline genetic variation in the APOE gene impacts melanoma progression through disparate mechanisms.
“Taken together, our work further highlights how germline genetic variation in the APOE gene impacts melanoma progression through disparate mechanisms.”
Quote in the paperSubstantial claim - Interpretationown data
The APOE receptor LRP1 is necessary for the pro-tumorigenic and pro-metastatic activity of APOE2.
“We identified the APOE receptor LRP1 as necessary for the pro-tumorigenic and pro-metastatic activity of APOE2.”
Quote in the paperSubstantial claim - Interpretationcitation
LRP1 is suitable for mediating signals that could impact protein synthesis.
“LRP1 is a well-established regulator of intracellular signaling (45), thus making it suitable for mediating signals that could impact protein synthesis.”
Quote in the paperNot a substantial claim
- May combine two claims. 30
- Classified as probably not a substantial claim. 24
May combine two claims.
PremisecitationThe BPC model enables tamoxifen-inducible deletion of Pten tumor suppressor and activation of BrafV600E oncogene specifically in melanocytes, resulting in melanoma formation in 3-4 weeks with 100% penetrance and recapitulation of the entirety of the metastatic cascade.
“The BPC model enables tamoxifen-inducible deletion of the Pten tumor suppressor and activation of the BrafV600E oncogene specifically in melanocytes, resulting in melanoma formation in 3–4 weeks with 100% penetrance and recapitulation of the entirety of the metastatic cascade (6).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Dankort, 2009, Braf(V600E) cooperates with Pten loss to induce metastatic melanoma, Nat Genet source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationThe cell-intrinsic effect of APOE on melanoma invasiveness is variant dependent, with APOE4 most potently suppressing invasion relative to APOE2.
“This cell-intrinsic effect was also variant dependent, with APOE4 most potently suppressing invasion relative to APOE2 (3).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Ostendorf, 2020, Common germline variants of the human APOE gene modulate melanoma progression and survival, Nat Med source
May combine two claims.
PremisecitationMelanoma patients who carry an APOE4 allele exhibit improved survival whereas APOE2 carriers experience poorer outcomes in multiple large cohorts.
“melanoma patients who carry an APOE4 allele exhibit improved survival whereas APOE2 carriers experience poorer outcomes in multiple large cohorts.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Ostendorf, 2020, Common germline variants of the human APOE gene modulate melanoma progression and survival, Nat Med source
The main text (page unavailable in our copy) reports significantly longer survival for APOE4 carriers than APOE2 carriers in the TCGA melanoma cohort, and the same ordering in two anti-PD1 treatment studies. The independent MDACC cohort supports the APOE2 finding only among patients at high risk of melanoma-associated death; APOE2 carriers at low risk trended toward better survival. The claim omits that qualification when describing outcomes across cohorts. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationAPOE has a cell-intrinsic effect in suppressing melanoma cell invasiveness.
“In addition to tumor cell-extrinsic effects on the immune and vascular compartments, prior work also identified a cell-intrinsic effect of APOE in suppressing of melanoma cell invasiveness (4).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] Pencheva, 2012, Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis, Cell source
May combine two claims.
PremisecitationThe variant-dependent effects of APOE on melanoma progression are partly governed by differences in anti-tumor immunity, as stromal expression of APOE4 confers increased immune effector responses relative to APOE2.
“The variant-dependent effects of APOE on melanoma progression are partly governed by differences in anti-tumor immunity, as stromal expression of APOE4 confers increased immune effector responses relative to APOE2.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Ostendorf, 2020, Common germline variants of the human APOE gene modulate melanoma progression and survival, Nat Med source
May combine two claims.
InterpretationcitationThe lack of difference in CD8+ T cell infiltration is likely because the BPC GEMM is a poorly immunogenic mouse model, which may preclude immune differences from developing by this time point.
“This is likely because the BPC GEMM is a poorly immunogenic mouse model (26), which may preclude immune differences from developing by this time point.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [26] Wang, 2017, UV-induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model, Pigment Cell Melanoma Res source
The Methods identify YUMM1.7 as derived from a melanoma with BrafV600E, Pten−/− and Cdkn2a−/− alterations. The Discussion says YUMM1.7 showed similar growth with or without a functional adaptive immune system, consistent with weak immunogenicity. The paper studies implanted cell-line tumors, however, rather than establishing the immunogenicity of the BPC genetically engineered mouse model itself. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationAPOE4 has been shown to enhance anti-tumor effector immune cell activity in melanoma.
“As APOE4 has been shown to enhance anti-tumor effector immune cell activity in melanoma (3), we evaluated the contribution of anti-tumor immunity to the observed growth differences between BPC/APOE2 and BPC/APOE4 tumors.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Ostendorf, 2020, Common germline variants of the human APOE gene modulate melanoma progression and survival, Nat Med source
Classified as probably not a substantial claim.
PremisecitationAPOE protein acts extracellularly on tumoral APOE receptors.
“APOE protein is known to act extracellularly on tumoral APOE receptors, and both tumor-derived and stroma-derived APOE have been found to regulate melanoma metastatic capacity in this manner (4,5).”
Quote in the paperSubstantial claim1 of 2 sources checkedMay combine two claims.
PremisecitationAPOE4 carriers have a survival advantage relative to APOE3 patients while APOE2 carriers experience worse survival outcomes.
“The TCGA-SKCM dataset was previously used to determine that APOE4 carriers have a survival advantage relative to APOE3 patients while APOE2 carriers experience worse survival outcomes (3).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Ostendorf, 2020, Common germline variants of the human APOE gene modulate melanoma progression and survival, Nat Med source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMost oncogenic signaling pathways converge to enhance the translational capacity of tumor cells.
“Translational control plays a critical role in all steps of cancer progression, and most oncogenic signaling pathways converge to enhance the translational capacity of tumor cells (30–32).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [30] Truitt, 2016, New frontiers in translational control of the cancer genome, Nat Rev Cancer source
- cites [31] Knight, 2021, MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression, Cancer Discov source
The Introduction says that many oncogenic pathways signal to eIF4E phosphorylation and that KRAS activation enhances protein synthesis. It supports a link between oncogenic signaling and translation, but does not establish that most oncogenic pathways converge to enhance tumor cells’ translational capacity. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [32] Krishnamoorthy, 2019, EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC, Cancer Discov source
The Introduction says deregulated translation initiation is common in cancer, and the Discussion reports increased global protein synthesis in thyroid cancer cells with EIF1AX and RAS mutations. Those passages support a link between oncogenic changes and translation, but do not establish that most oncogenic signaling pathways converge to enhance translational capacity. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAPOE3 is the most common APOE variant in the human population.
“APOE3 served as an ideal isogenic control for determining whether APOE2 mediates translational enhancement because it exhibited an intermediate phenotype in our GEMM studies and is the most common APOE variant in the human population (7).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [7] Belloy, 2019, A quarter century of APOE and Alzheimer's disease: progress to date and the path forward, Neuron source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTranslational control plays a critical role in all steps of cancer progression.
“Translational control plays a critical role in all steps of cancer progression, and most oncogenic signaling pathways converge to enhance the translational capacity of tumor cells (30–32).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [30] Truitt, 2016, New frontiers in translational control of the cancer genome, Nat Rev Cancer source
- cites [31] Knight, 2021, MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression, Cancer Discov source
The Introduction says that deregulated mRNA translation sustains cancer-cell proliferation and oncogene expression, and that eIF4E phosphorylation is downstream of many oncogenic pathways. It does not establish a critical role for translational control in all steps of cancer progression, or that most oncogenic pathways converge to enhance tumor cells’ translational capacity. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [32] Krishnamoorthy, 2019, EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC, Cancer Discov source
The Introduction (page unavailable) says deregulation of translation initiation is common in tumorigenesis, and the Discussion describes increased protein synthesis driven by EIF1AX and RAS mutations in thyroid cancer. The paper does not establish that translational control is critical at all steps of cancer progression or that most oncogenic signaling pathways converge to enhance tumor-cell translational capacity. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationAPOE4 represses melanoma progression via its suppression of multiple cancer phenotypes including invasion, angiogenesis and immune evasion.
“We propose a model in which APOE2 and APOE4 carry out opposing functions in melanoma, with APOE2 promoting growth, metastasis, and protein translation via the LRP1 receptor and APOE4 repressing progression via its suppression of multiple cancer phenotypes including invasion, angiogenesis and immune evasion, as demonstrated in previous work (3) (Fig. 4D).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Ostendorf, 2020, Common germline variants of the human APOE gene modulate melanoma progression and survival, Nat Med source
May combine two claims.
PremisecitationThe TCGA-SKCM cohort contains over 400 patients with both RNA sequencing and whole exome sequencing data, enabling differential gene expression analysis of human tumors based on the germline APOE genotype.
“The Cancer Genome Atlas skin cutaneous melanoma (TCGA-SKCM) cohort contains over 400 patients with both RNA sequencing and whole exome sequencing data, enabling differential gene expression analysis of human tumors based on the germline APOE genotype (36) (Fig. 4A).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [36] Cancer Genome Atlas Network, 2015, Genomic classification of cutaneous melanoma, Cell source
The Results section, “Multi-dimensional Genomic Characterization of Cutaneous Melanoma” (page unavailable), reports both whole-exome sequencing and mRNA sequencing. But “Data Generation” says data from at least one platform were available for only 333 patients, so this paper does not support over 400 patients having both. It reports paired germline DNA sequencing but does not describe differential expression analysis by germline APOE genotype. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationAPOE is a potent suppressor of melanoma metastasis.
“Because APOE is a potent suppressor of melanoma metastasis (4), we next evaluated whether genetic variation in APOE could modulate metastatic capacity in the BPC GEMM.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] Pencheva, 2012, Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis, Cell source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLRP1 is a well-established regulator of intracellular signaling.
“LRP1 is a well-established regulator of intracellular signaling (45), thus making it suitable for mediating signals that could impact protein synthesis.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [45] Boucher, 2011, Signaling through LRP1: protection fr2om atherosclerosis and beyond, Biochem Pharmacol source
May combine two claims.
PremisecitationCausal somatic mutational drivers of metastasis have not been identified despite extensive sequencing efforts, suggesting that alternative mechanisms may underlie propensity for metastatic progression.
“Although long speculated to exist, causal somatic mutational drivers of metastasis have not been identified despite extensive sequencing efforts, suggesting that alternative mechanisms may underlie propensity for metastatic progression (46).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [46] Vogelstein, 2013, Cancer genome landscapes, Science source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe molecular mechanisms underlying the link between APOE genotype and Alzheimer's disease risk remain elusive.
“Despite nearly 30 years of research following the discovery that APOE genotype impacts Alzheimer’s disease risk, the molecular mechanisms underlying this link remain elusive (7).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [7] Belloy, 2019, A quarter century of APOE and Alzheimer's disease: progress to date and the path forward, Neuron source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAPOE has diverse roles in numerous biological processes including lipid metabolism, immunity, mitochondrial function, and neuronal repair.
“This is a product of the pronounced complexity of APOE, which has diverse roles in numerous biological processes including lipid metabolism, immunity, mitochondrial function, and neuronal repair (7,37).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [7] Belloy, 2019, A quarter century of APOE and Alzheimer's disease: progress to date and the path forward, Neuron source
The ‘Role of APOE in Alzheimer’s Disease Pathogenesis’ section describes APOE’s lipid transport, cholesterol delivery for neuronal repair, and involvement in immune regulation. The ‘APOE and Ancestral Background’ section also discusses a potential role in innate immunity. The copy does not establish a role for APOE in mitochondrial function; ‘mitochondrial’ appears only in a cited work’s title in the References. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [37] Huang, 2014, Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases, Neurobiol Dis source
The Introduction describes apoE’s role in lipid transport, and the neurobiology section links it to peripheral nerve repair. The paper also describes effects on mitochondrial function. It reports apoE production by macrophages and an apoE4-linked proinflammatory pathway, but does not clearly establish the broader claimed role in immunity. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationThe pleiotropic behavior of APOE also applies to melanoma, and APOE2 can act as a gain-of-function allele in a disease context.
“Our study adds to an increasing body of evidence that the pleiotropic behavior of APOE also applies to melanoma (3,4) and supports the notion that APOE2 can act as a gain-of-function allele in a disease context.”
Quote in the paperSubstantial claim2 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationIt has been unclear whether the APOE alleles represent a progressive gain or loss of function of the APOE protein, as the risk of APOE-influenced diseases other than Alzheimer's does not always follow an APOE4>APOE3>APOE2 order.
“It has also been unclear whether the APOE alleles represent a progressive gain or loss of function of the APOE protein, as the risk of APOE-influenced diseases other than Alzheimer’s does not always follow an APOE4>APOE3>APOE2 order (7).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Belloy, 2019, A quarter century of APOE and Alzheimer's disease: progress to date and the path forward, Neuron source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNeuronal protein synthesis is crucial for synaptic function and memory formation, and it is dysregulated in Alzheimer's.
“Neuronal protein synthesis has been well established as crucial for synaptic function and memory formation, and it is dysregulated in Alzheimer’s (43).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [43] Buffington, 2014, Translational control in synaptic plasticity and cognitive dysfunction, Annu Rev Neurosci source
May combine two claims.
Findingown datamRNA translation is a melanoma cell-intrinsic process that is modulated by APOE, with APOE2 acting as a promoter of protein synthesis.
“Additionally, we identified mRNA translation as a melanoma cell-intrinsic process that is modulated by APOE, with APOE2 acting as a promoter of protein synthesis.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMelanomas grew faster and were significantly larger at the day 49 endpoint in BPC/APOE2 mice relative to BPC/APOE4 mice.
“In an independent cohort of mice whose tumor growth rate was tracked, melanomas grew faster (Fig. 1E) and were significantly larger at the day 49 endpoint (Fig. 1F) in BPC/APOE2 mice relative to BPC/APOE4 mice—consistent with the aforementioned findings.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMouse survival followed a similar pattern, with BPC/APOE2 mice having the shortest median survival at 42.5 days, BPC/APOE3 mice intermediate at 53.5 days, and BPC/APOE4 mice having the longest survival at 59.5 days.
“Mouse survival followed a similar pattern, with BPC/APOE2 mice having the shortest median survival at 42.5 days, BPC/APOE3 mice intermediate at 53.5 days, and BPC/APOE4 mice having the longest survival at 59.5 days (Fig. 1D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHistological analysis of a representative pigmented lesion revealed features consistent with metastatic melanoma on H&E staining and positive staining for S100.
“Histological analysis of a representative pigmented lesion revealed features consistent with metastatic melanoma on hematoxylin and eosin (H&E) staining as well as positive staining for S100, a sensitive marker for melanoma (Supplementary Fig. S1E).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataTumors in this melanoma GEMM progressed in an APOE2>APOE3>APOE4 manner, consistent with melanoma patient survival outcomes.
“Tumors in this melanoma GEMM progressed in an APOE2>APOE3>APOE4 manner, consistent with melanoma patient survival outcomes.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAPOE2 has clear gain-of-function effects in both protein translation and the promotion of melanoma progression.
“Our findings reveal clear gain-of-function effects for APOE2 in both protein translation and the promotion of melanoma progression.”
Quote in the paperSubstantial claim- Rests on an assumption: The effects of human APOE variants on melanoma progression in the BPC GEMM reflect their effects in human melanoma patients.
- Rests on an assumption: GEMMs recapitulate all steps of the cancer progression cascade from tumor initiation through to metastatic colonization, and the genetics of the tumor match that of the host.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFour independent fields per tumor section were imaged at random with consistent instrument settings between samples.
“Four independent fields per tumor section were imaged at random with a Nikon A1R MP confocal microscope (RRID:SCR_020319) with consistent instrument settings between samples.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCells were regularly tested for Mycoplasma contamination.
“All cells were maintained in an incubator at 37°C and 5% CO2 and regularly tested for Mycoplasma contamination with the Universal Mycoplasma Detection Kit (ATCC, 30–1012K).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationPast studies revealed an APOE4>APOE3>APOE2 pattern of melanoma tumor suppression.
“These past studies revealed an APOE4>APOE3>APOE2 pattern of melanoma tumor suppression.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataProtein overexpression was validated by western blot.
“Protein overexpression was validated by western blot.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataLRP1 knockout was confirmed via western blot.
“LRP1 knockout was confirmed via western blot.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal experiments were conducted in accordance with a protocol approved by the Institutional Animal Care and Use Committee at The Rockefeller University.
“All animal experiments were conducted in accordance with a protocol (#20010) approved by the Institutional Animal Care and Use Committee at The Rockefeller University.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe higher APOE2 expression is likely due to feedback compensation for reduced binding of APOE2 to APOE receptors.
“and is likely due to feedback compensation for reduced binding of APOE2 to APOE receptors (24,25).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSections stained with secondary antibody alone were used as negative controls.
“Sections stained with secondary antibody alone were used as negative controls.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenThe number of pigmented lesions on the surface of each lung was quantified in a blinded manner.
“The number of pigmented lesions on the surface of each lung was quantified in a blinded manner under high magnification.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningAPOE2-mediated enhancement of translation supports melanoma growth and metastasis in APOE2 carriers, consistent with their poor survival compared to both APOE3 homozygotes and APOE4 carriers.
“Taken together with our findings from mouse modeling, we propose that APOE2-mediated enhancement of translation—a key driver of tumor growth and metastasis—supports melanoma growth and metastasis in APOE2 carriers, consistent with their poor survival compared to both APOE3 homozygotes and APOE4 carriers.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningLRP1 likely mediates downstream molecular events that are preferentially activated by APOE2 and remain to be identified.
“LRP1 thus likely mediates downstream molecular events that are preferentially activated by APOE2 and remain to be identified.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataRNA integrity numbers were measured with an Agilent Bioanalyzer 2100, with an average RIN of 8.15.
“RNA integrity numbers (RIN) were measured with an Agilent Bioanalyzer 2100 (RRID:SCR_018043), with an average RIN of 8.15.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataRNA quality was assessed with an Agilent Bioanalyzer 2100, with an average RIN of 8.58.
“RNA quality was assessed with an Agilent Bioanalyzer 2100, with an average RIN of 8.58.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThese results indicate that Lrp1 deletion significantly abrogates the impact of APOE variants on melanoma progression, with differences only emerging when the cell-extrinsic effects of APOE become impactful at later primary tumor stages in the genetic model.
“These results indicate that Lrp1 deletion significantly abrogates the impact of APOE variants on melanoma progression, with differences only emerging when the cell-extrinsic effects of APOE become impactful at later primary tumor stages in the genetic model.”
Quote in the paperSubstantial claim- Rests on an assumption: Transplantable mouse models are limited in their ability to recapitulate all steps of the metastatic cascade.
May combine two claims.
InterpretationreasoningAPOE2 promotes growth, metastasis, and protein translation via the LRP1 receptor.
“We propose a model in which APOE2 and APOE4 carry out opposing functions in melanoma, with APOE2 promoting growth, metastasis, and protein translation via the LRP1 receptor and APOE4 repressing progression via its suppression of multiple cancer phenotypes including invasion, angiogenesis and immune evasion, as demonstrated in previous work (3) (Fig. 4D).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThese findings are consistent with a model whereby APOE2 promotes translation rather than APOE4 inhibiting translation.
“These findings are consistent with a model whereby APOE2 promotes translation rather than APOE4 inhibiting translation.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe higher puromycin incorporation in BPC/APOE2 tumors is indicative of either a slower translation rate in the APOE4 background or enhanced translation rate in the APOE2 background.
“Consistent with our RNA-Seq results, BPC/APOE2 tumors exhibited significantly higher puromycin incorporation than BPC/APOE4 tumors, indicative of either a slower translation rate in the APOE4 background or enhanced translation rate in the APOE2 background (Fig. 2C).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThese results indicate that the APOE variants differentially impact melanoma protein synthesis, with APOE2 stimulating translation in both localized and metastatic melanoma.
“These results indicate that the APOE variants differentially impact melanoma protein synthesis, with APOE2 stimulating translation in both localized and metastatic melanoma.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataBPC/APOE2 and BPC/APOE4 mice were injected with puromycin 35 days after 4-OHT administration, an early time point at which a significant difference in tumor volumes was not yet detectable.
“To control for tumor size differences, BPC/APOE2 and BPC/APOE4 mice were injected with puromycin 35 days after 4-OHT administration, an early time point at which a significant difference in tumor volumes was not yet detectable (Supplementary Fig. S2A).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningEnhancement of translation may contribute to the protective effect of APOE2 in Alzheimer's and may partly explain the inverse impact of APOE variants in melanoma versus Alzheimer's disease.
“Thus, enhancement of translation may contribute to the protective effect of APOE2 in Alzheimer’s and may partly explain the inverse impact of APOE variants in melanoma versus Alzheimer’s disease.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningOur findings provide support for germline genetic variants as causal contributors to metastatic outcomes, revealing hereditary genetics as a predictor of cancer progression.
“Our findings provide support for germline genetic variants as causal contributors to metastatic outcomes—revealing hereditary genetics as a predictor of cancer progression and providing new avenues for mechanistic and therapeutic studies.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown datamRNA translation is an oncogenic process that is actively enhanced by APOE2, expanding the mechanism of differential modulation beyond anti-tumor immunity, angiogenesis, and cellular invasion.
“We expand the mechanism of this differential modulation beyond anti-tumor immunity, angiogenesis, and cellular invasion by identifying mRNA translation as an oncogenic process that is actively enhanced by APOE2.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The impact of germline genetics on the progression of cancers once they are established is poorly understood.
“In contrast, the impact of germline genetics on the progression of cancers once they are established is poorly understood.”
The paper relies on this without support.
The impact of APOE variants on intracellular processes that could contribute to cancer growth and metastasis outcomes has remained uncharacterized.
“While this past work led to the identification of multiple cellular and organismal cancer progression phenotypes that are differentially associated with APOE variants, the impact of APOE variants on intracellular processes that could contribute to cancer growth and metastasis outcomes has remained uncharacterized.”
The paper relies on this without support.
The effects of human APOE variants on melanoma progression in the BPC GEMM reflect their effects in human melanoma patients.
“Using a genetically engineered mouse model, we showed that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner.”
The paper relies on this without support.
GEMMs recapitulate all steps of the cancer progression cascade from tumor initiation through to metastatic colonization, and the genetics of the tumor match that of the host.
“In contrast to transplantable models, GEMMs recapitulate all steps of the cancer progression cascade from tumor initiation through to metastatic colonization, and the genetics of the tumor match that of the host.”
The paper relies on this without support.
Transplantable mouse models are limited in their ability to recapitulate all steps of the metastatic cascade.
“As described earlier, transplantable mouse models are limited in their ability to recapitulate all steps of the metastatic cascade.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A recent study indicated that in melanoma cells, particularly the ApoE2 isoform among the top up-regulated pathways, increased the expression of genes involved in selenoamino acid metabolism and protein translation machinery.
“A recent study indicated that in melanoma cells, particularly the ApoE2 isoform among the top up-regulated pathways, increased the expression of genes involved in selenoamino acid metabolism and protein translation machinery (57).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [57]
The Results section (‘Genetically engineered mouse model reveals protein translation upregulation in APOE2 tumors’; page unavailable) reports that translation and other protein-synthesis pathways were among the top upregulated pathways in APOE2 tumors. The provided passages and a search of our copy for ‘selenoamino acid metabolism’ do not establish the claimed increase in genes involved in that pathway. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward
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Self-citationHighly penetrant hereditary cancer syndromes
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New frontiers in translational control of the cancer genome
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APOE distribution in world populations with new data from India and the UK
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β-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas
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Translational control in synaptic plasticity and cognitive dysfunction
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Apo E structure determines VLDL clearance and atherosclerosis risk in mice
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Erratum: New frontiers in translational control of the cancer genome
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Elucidating Distinct Roles for <i>NF1</i> in Melanomagenesis
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Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53
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Measuring Protein Synthesis With SUnSET: A Valid Alternative to Traditional Techniques?
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<i>Atg7</i> Overcomes Senescence and Promotes Growth of <i>Braf</i> V600E-Driven Melanoma
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Wang, J., Perry, C. J., Meeth, K., Thakral, D., Damsky, W., Micevic, G., Kaech, S., Blenman, K., & Bosenberg, M. (2017) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12591 · Cited by 199 · see citing works
Pencheva, N., Buss, C. G., Posada, J., Merghoub, T., & Tavazoie, S. F. (2014) · Cell · doi:10.1016/j.cell.2014.01.038 · Cited by 175 · see citing works
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Plasma levels of apolipoprotein <scp>E</scp> and risk of dementia in the general population
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Signaling through LRP1: Protection from atherosclerosis and beyond
Boucher, P., & Herz, J. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.09.018 · Cited by 122 · see citing works
Common germline variants of the human APOE gene modulate melanoma progression and survival
Ostendorf, B. N., Bilanovic, J., Adaku, N., Tafreshian, K. N., Tavora, B., Vaughan, R. D., & Tavazoie, S. F. (2020) · Nature Medicine · doi:10.1038/s41591-020-0879-3 · Cited by 108 · see citing works
Self-citationMelanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis
Kleffman, K., Levinson, G., Rose, I. V. L., Blumenberg, L. M., Shadaloey, S. A. A., Dhabaria, A., Wong, E., Galán-Echevarría, F., Karz, A., Argibay, D., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1006 · Cited by 100 · see citing works
Knight, J. R. P., Alexandrou, C., Skalka, G. L., Vlahov, N., Pennel, K., Officer, L., Teodosio, A., Kanellos, G., Gay, D. M., May-Wilson, S., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0652 · Cited by 96 · see citing works
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APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain
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Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer's Disease
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A Simple, Reliable and Inexpensive Method to Individually Identify Neonate Mice.
Westmark, P. R., Gutierrez, A., & Westmark, C. J. (2021) · PubMed · Cited by 4 · see citing works
Flagged first, then by citations
2 of the 53 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor
Mei, W., Tabrizi, S. F., Godina, C., Lovisa, A. F., Isaksson, K., Jernström, H., & Tavazoie, S. F. (2024) · Cell · doi:10.1016/j.cell.2024.11.009 · Cited by 40 · see citing works
Self-citationSecreted Apoe rewires melanoma cell state vulnerability to ferroptosis
More, S., Bonnereau, J., Wouters, D., Spotbeen, X., Karras, P., Rizzollo, F., Killian, T., Venken, T., Naulaerts, S., Vervoort, E., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp6164 · Cited by 25 · see citing works
“A recent study indicated that in melanoma cells, particularly the ApoE2 isoform among the top up-regulated pathways, increased the expression of genes involved in selenoamino acid metabolism and protein translation machinery ( 57 ).”
Ersöz, N. Ş., Bakır-Güngör, B., & Yousef, M. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1139082 · Cited by 21 · see citing works
Meta-analysis reveals an inverse relationship between Alzheimer’s disease and cancer
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YO2 Induces Melanoma Cell Apoptosis through p53-Mediated LRP1 Downregulation
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“APOE2/LRP1 axis may play important roles in tumor growth, metastasis, and protein synthesis in melanoma [197]. miR-103 and miR-107 are miRNAs related to each other, with a difference of just one base in their 3’ regions [198].”
Decoding the role of LRP1 in cancers: From molecular mechanisms to therapeutic opportunities
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Exploring the evolving role of apolipoproteins in oncology: global trends and emerging frontiers
Tian, D., Hu, Z., Yang, Z., Zhao, L., Zhao, H., Sang, X., Du, S., Luo, Y., Zhang, L., Xu, Y., et al. (2025) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-025-06360-1 · Cited by 1 · see citing works
The role of APOE gene polymorphisms in lung adenocarcinoma susceptibility and lipid profile
Bi, H., Ren, D., Wang, Y., Wang, H., & Zhang, C. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1522761
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“IHC analysis further con fi rmed that APOE expression was signi fi cantly reduced in OS tissues, supporting the transcriptome-based fi ndings and strengthening the evidence that APOE is dysregulated in the OS microenvironment (10).”
Apolipoprotein E and liver health: Implications in lipid metabolism and diseases
Alam, Q., Ganeshpurkar, A., & El‐Zahaby, S. A. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-40563-1.00016-8
- Authors
- Adaku, N., Ostendorf, B. N., Mei, W., & Tavazoie, S. F.
- Affiliations
- Rockefeller University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Tavazoie, Sohail F.
- Venue
- Cancer Research
- Published
- 2023-06-19
- Volume
- 83
- Issue
- 18
- Pages
- 3013-3025
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC10740391
- OpenAlex
- W4381144485
- Cited by
- 15
- References
- 53
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 1 · 2022: 1
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Cancer Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM007739)
- National Cancer Institute (F30CA257226, R01CA184804, R35CA274446, U54CA261701)
- Melanoma Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- apolipoprotein E, APOE2, APOE ε4, melanoma progression, melanoma metastasis, protein synthesis, translation (biology), germline genetic variants, lipid transport, genetic risk prediction
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Carrier Proteins, Humans, Melanoma, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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