Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis
Open accessAbstract
Through in vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target apolipoprotein E (ApoE) and the heat shock factor DNAJA4. Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma cell LRP1 and endothelial cell LRP8 receptors, respectively, while DNAJA4 promotes ApoE expression. Expression levels of these miRNAs and ApoE correlate with human metastatic progression outcomes. Treatment of cells with locked nucleic acids (LNAs) targeting these miRNAs inhibits metastasis to multiple organs, and therapeutic delivery of these LNAs strongly suppresses melanoma metastasis. We thus identify miRNAs with dual cell-intrinsic/cell-extrinsic roles in cancer, reveal convergent cooperativity in a metastatic miRNA network, identify ApoE as an anti-angiogenic and metastasis-suppressive factor, and uncover multiple prognostic miRNAs with synergistic combinatorial therapeutic potential in melanoma.
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Mechanisms underlying the association between high apoE levels and increased cancer mortality could likely be due to apoE involvement in metastasis and angiogenesis.
“mechanisms underlying the association between high apoE levels and increased cancer mortality could likely be due to apoE involvement in metastasis and angiogenesis.49–56”
From Plasma levels of apolipoprotein E, <i>APOE</i> genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort (2019) · cites this paper as [50]
The Discussion says ApoE suppresses melanoma metastatic progression and suggests that increasing ApoE levels could reduce melanoma mortality. The Results also identify systemic ApoE as a suppressor of metastatic angiogenesis. These findings point in the opposite direction from the proposed explanation for increased mortality with high ApoE levels. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredOur findings are consistent with past biochemical observations of enhanced (APOE4) and reduced (APOE2) APOE function in cancer, given the previously described roles of APOE in suppressing innate immune suppression, invasiveness, and endothelial recruitment.
“Our findings in this report are consistent with these past biochemical observations of enhanced (APOE4) and reduced (APOE2) APOE function in cancer, given the previously described roles of APOE in suppressing innate immune suppression, invasiveness, and endothelial recruitment4,12.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [12]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredTumoral and stroma-derived APOE suppresses melanoma progression.
“We previously reported that tumoral and stroma-derived APOE suppresses melanoma progression4,12,13.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [12]
The Results section on genetic inactivation reports that both cancer-secreted and systemic ApoE suppress melanoma metastasis. That supports the tumoral component, but the paper does not establish that the protective systemic ApoE is specifically stroma-derived; no page number is available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredStroma-derived APOE expression is dictated by the genetics of the host.
“In contrast to tumoral APOE, for which expression becomes repressed during melanoma progression, stroma-derived APOE expression is dictated by the genetics of the host12.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [12]
In Results, “Genetic inactivation of ApoE promotes metastasis” (page unavailable), the paper compares ApoE-null and wild-type host mice and identifies a role for systemic ApoE. It does not measure stroma-derived APOE expression or establish that its expression is dictated by host genetics; that more specific part of the claim is unsupported. (LLM, conf=0.79)
Experimental — accuracy not yet measuredAPOE4 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).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [4]
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
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).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [4]
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 measuredApoE impedes melanoma cell invasiveness and endothelial cell recruitment, thereby serving as a key barrier to metastatic colonization.
“We observed that ApoE impedes melanoma cell invasiveness and endothelial cell recruitment—two metastatic phenotypes—thereby serving as a key barrier to metastatic colonization.”
From LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer (2018) · cites this paper as Pencheva et al., 2012
ApoE mediates its effects on endothelial migration via the LRP8 ApoE receptor.
“We had previously observed that ApoE mediates its effects on endothelial migration via the LRP8 ApoE receptor”
From LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer (2018) · cites this paper as Pencheva et al., 2012
APOE 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).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [4]
APOE 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).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [4]
APOE 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.”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [4]
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).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [4]
The 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.”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [4]
In melanoma, ApoE is known to modulate the metastatic potential of melanoma cells by engaging with LRP1 and LRP8 receptor proteins.
“In melanoma, ApoE is known to modulate the metastatic potential of melanoma cells by engaging with LRP1 and LRP8 receptor proteins (21).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [21]
ApoE is known to be secreted by cancer cells.
“apolipoprotein E (ApoE), which is known to be secreted by cancer cells87”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [87]
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Self-citation
- Authors
- Pencheva, N., Tran, H., Buss, C., Huh, D., Drobnjak, M., Busam, K., & Tavazoie, S. F.
- Affiliations
- Rockefeller University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Tavazoie, Sohail F.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 151
- Issue
- 5
- Pages
- 1068-1082
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3753115
- OpenAlex
- W2060088882
- Cited by
- 415
- References
- 4
- Citations by year
- 2026: 14 · 2025: 30 · 2024: 30 · 2023: 31 · 2022: 37 · 2021: 37 · 2020: 32 · 2019: 25 · 2018: 26 · 2017: 28 · 2016: 30 · 2015: 43 · 2014: 32 · 2013: 19 · 2012: 1
- FWCI
- 9.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- Melanoma Research Alliance
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health
- National Center for Research Resources (KL2RR024142)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- melanoma metastasis, angiogenesis, miRNA network, miR-199a-5p, miR-199a-3p, apolipoprotein E, heat shock transcription factor, LRP1, LRP8, prognostic factors
- MeSH terms
- Animals, Apolipoproteins E, Cells, Cultured, Disease Models, Animal, Humans, Melanoma, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Neovascularization, Pathologic, Oligonucleotides, Gene Expression Regulation, Neoplastic, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-1, MicroRNAs, Endothelial Cells, Cell Line, Tumor, HSP40 Heat-Shock Proteins, Mice
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