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Cited by 17Liver physiology and pathologyPluripotent Stem Cells ResearchDevelopmental Biology and Gene Regulation

Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis

Open access
Lim, Bryce, Kamal, Aryan, Gomez Ramos, Borja, Adrian Segarra, Juan M., Ibarra, Ignacio L., Dignas, Lennart, Kindinger, Tim, Volz, Kai +21 more·2025·Nature Genetics
DOI 10.1038/s41588-025-02081-wPMC PMC11906372

Published version of a preprint

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Abstract

Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.

AI snapshot

Written from the paper’s full text.

TL;DR

The paper computationally identifies cell-type-specific “safeguard repressors” across 18 cell types and validates PROX1 as a hepatocyte safeguard that actively represses alternative fate master regulators. PROX1 loss unlocks hepatocyte plasticity, impairs regeneration, and promotes HCC-to-CCA transition, while PROX1 gain suppresses liver tumor initiation/progression and drives CCA-to-HCC transdifferentiation.

Key findings

  • A safeguard repressor screen across 18 cell types and 1,296 TFs shortlisted 59 candidates; 27 satisfied lifelong safeguard criteria, 14 were reported to promote the predicted cell fate, and 59% (16/27) had reported tumor-suppressive roles.
  • PROX1 was the top hepatocyte candidate: PROX1 overexpression increased hepatocyte-like induction greater than tenfold by TJP1 and elevated albumin secretion per cell 17-fold; Prox1 deletion reduced TJP1-positive hepatocyte-like cells greater than sevenfold and impaired liver regeneration, with HNF4+ hepatocytes reduced by ~33% and serum ALP elevated twofold.
  • PROX1 suppressed liver cancer in mice: in Myc/Trp53 HCC, constitutive Prox1 OE reduced nodules from 39.5 to 6.7 and increased median survival from 29 to 64 days; late Prox1 OE reduced GFP+ nodules from 219.5 to 13.75 and increased median survival from 17 to 36.5 days; in Kras/Trp53, nodules fell from 19.5 to 3.25 and survival rose from 26.5 to 47.5 days; in Akt/Notch CCA, nodules fell from 245.2 to 59.8 and survival rose from 54 to 88 days.
  • PROX1 controls HCC versus CCA fate: PROX1 expression was 1.4-fold higher in HCC than CCA; Prox1 knockdown shifted HCC toward CCA, while Prox1 overexpression shifted CCA toward HCC. PROX1 bound and repressed alternative master regulators, including PRRX1 and PPARG, and interacted with 11 of 14 NuRD complex members in liver but not brain.

Methods

  • Computational safeguard repressor screen using Tabula Muris single-cell data for 18 cell types, 1,296 TFs, cell-type-specific expression, DNA-binding motif enrichment/depletion at signature genes, and lifelong expression from Tabula Muris Senis and developmental atlases; score combined Zexpression and −Zmotif.
  • Experimental validation used MEF reprogramming toward hepatocytes (4-in-1), neurons (Ascl1), and myocytes (Myod1), with Prox1 overexpression, knockdown, conditional knockout, domain-fusion constructs, CUT&RUN, ATAC–seq, bulk RNA-seq, single-cell RNA-seq, and immunoprecipitation–mass spectrometry.
  • In vivo work used HDTVI mouse liver cancer models (Myc/Trp53, Kras/Trp53, Akt/Notch), DDC-induced liver injury in Prox1fl/fl mice, human HCC/CCA expression and survival data, and Kaplan–Meier/log-rank survival analyses.

Limitations

  • The paper states that its model for safeguard repressors is “speculative” and that further studies are needed to test whether other TFs guard cell fate in a similar cofactor-dependent manner.
  • Evident from the text: the computational screen was experimentally validated only for hepatocyte candidates, so the function of most of the 27 predicted safeguard repressors remains untested.
  • Evident from the text: PROX1’s role is context-dependent—it can act as an activator in brain and lymphatic endothelium and has reported tumor-promoting effects upon transplantation—and the survival benefit comparisons to sorafenib are indirect, drawn from comparable models rather than direct head-to-head experiments.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41588-025-02081-w

Cites

106 of 106 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

38 of 51 cited sources checked · 14 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    33 candidates exhibited continued expression in 2-year-old mice.

    “In total, 33 exhibited continued expression in 2-year-old mice16”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] The Tabula Muris Consortium, et al. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020). source

      The study description (section labelled Abstract; page unavailable) confirms that the atlas includes 24-month-old mice, and the Differential gene expression methods describe analyses of older age groups. Neither passage identifies 33 candidates with continued expression. Searches for “33,” “33 candidates expression 24m,” and “continued expression in 2-year-old mice” found no passage establishing that count. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Findingcitation

    77% (17/22) of heart, brain and liver candidates were expressed at high levels throughout development.

    “77% (17/22) of heart, brain and liver candidates were expressed at high levels throughout development17”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] Cardoso-Moreira, M. et al. Gene expression across mammalian organ development. Nature 571, 505–509 (2019). source

      The Organ developmental transcriptomes section and Extended Data Figure 1 discuss expression across development in organs including the heart, brain and liver, but neither reports a set of 22 candidates or says that 17 were highly expressed throughout development. Searches for “17/22,” “17 of 22,” “77%,” and candidate genes found no passage establishing the claimed result. Page numbers are not available in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Findingcitation

    In patients with HCC, chromosomal amplifications including PROX1 are associated with increased survival.

    “in patients with HCC, high PROX1 expression or chromosomal amplifications including PROX1 were both associated with increased survival25–32”
    Quote in the paperSubstantial claim7 of 8 sources checked
    • cites [25] Ahn, S.-M. et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 60, 1972–1982 (2014). source

      The Clinical Features section lists recurrent chromosomal amplifications in HCC, but does not identify PROX1 among them. The postsurgical-outcomes section links RB1 mutations—not PROX1 amplification—to survival. A search for PROX1 found no passage supporting the claimed association with increased survival; page numbers were unavailable in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [26] Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2, 401–404 (2012). source

      The paper’s Figure 1 caption discusses survival in glioblastoma, while its amplification examples concern glioblastoma and ovarian cancer. Searches for PROX1 and for HCC chromosomal amplifications with increased survival found no passage addressing the claimed association in patients with HCC. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [27] Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). source

      The Viewing and Interpreting the Results section describes survival analysis using BRCA1/BRCA2 mutations in ovarian cancer, not PROX1 amplification in HCC. Searches for PROX1 and for hepatocellular carcinoma or liver cancer found no passage addressing the claimed survival association in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [28] Harding, J. J. et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin. Cancer Res. 25, 2116–2126 (2019). source
    • cites [29] Ng, C. K. Y. et al. Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages. Nat. Commun. 13, 2436 (2022). source

      The Results section on copy-number alterations identifies recurrent amplifications and candidate driver genes, but does not identify PROX1. The molecular-subtypes Results section reports improved overall survival for certain clusters, without linking that outcome to amplifications involving PROX1. Searches for PROX1 and PROX1 amplification with survival found no passage supporting the attributed association. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [30] Weinstein, J. N. et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013). source

      The Limitations of Pan-Cancer Analysis section mentions hepatocellular carcinoma only in connection with viral causes. Searches for PROX1, HCC copy-number amplification, and survival found no passage linking amplifications including PROX1 to increased survival in HCC patients. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [31] Xue, R. et al. Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes. Cancer Cell 35, 932–947 (2019). source

      The Results section on copy-number alterations reports amplifications of several genes, but does not mention PROX1 or link those amplifications to survival. The Transcriptomic Comparison section reports survival differences between molecular clusters, not by PROX1 amplification. Searches for PROX1 and for its amplification–survival association found no supporting passage in our copy; page numbers were unavailable. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [32] Menyhárt, O., Nagy, Á. & Győrffy, B. Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma. R. Soc. Open Sci. 5, 181006 (2018). source

      The Results section reports HCC survival associations for other genes, but the passages retrieved by searching for PROX1 and chromosomal amplification do not identify a PROX1 amplification–survival association. The Discussion mentions copy-number gains of E2F1, not PROX1; our copy therefore does not address the specific claim. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Findingcitation

    In patients with HCC, high PROX1 expression is associated with increased survival.

    “in patients with HCC, high PROX1 expression or chromosomal amplifications including PROX1 were both associated with increased survival25–32”
    Quote in the paperSubstantial claim7 of 8 sources checked
    • cites [25] Ahn, S.-M. et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 60, 1972–1982 (2014). source

      The Clinical Features section discusses amplifications involving FGF19 and other genes, while the survival analysis in Genetic Aberrations in HCC concerns RB1 mutations. Searches for PROX1 expression and PROX1-containing amplifications found no passage linking PROX1 to survival. Page numbers were not available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [26] Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2, 401–404 (2012). source

      The portal description and Figure 1 discuss survival analysis for RB-pathway alterations in glioblastoma, not PROX1 in HCC (page not provided). Searches for PROX1, HCC, and the claimed expression–survival association found no passage in our copy addressing that association. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [27] Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). source

      The Instructions section, under Viewing and Interpreting the Results (page unavailable), reports a survival association for BRCA1/BRCA2 mutations in ovarian cancer, not PROX1 expression in HCC. Searches for PROX1, HCC and hepatocellular-carcinoma survival found no passage in our copy addressing the claimed association. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [28] Harding, J. J. et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin. Cancer Res. 25, 2116–2126 (2019). source
    • cites [29] Ng, C. K. Y. et al. Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages. Nat. Commun. 13, 2436 (2022). source

      The Results section on molecular subtypes reports survival associations for HCC clusters, but does not link survival to PROX1 expression. Searches for PROX1 and for amplifications including PROX1 returned no passage addressing that association in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [30] Weinstein, J. N. et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013). source

      The Pan-Cancer Project section discusses predicting patient outcomes across tumour types, while Limitations of Pan-Cancer Analysis mentions hepatocellular carcinoma only in relation to viral causes (page numbers unavailable). Searches for PROX1, HCC survival and chromosomal amplification found no passage linking PROX1 expression to survival in HCC patients. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [31] Xue, R. et al. Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes. Cancer Cell 35, 932–947 (2019). source

      The Results sections on Transcriptomic Comparison and Nestin Expression report survival associations for molecular clusters and Nestin, respectively; page numbers are unavailable in our copy. Searches for PROX1, PROX1 expression and survival, and PROX1 amplification and prognosis returned no passage linking PROX1 expression to survival in HCC. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [32] Menyhárt, O., Nagy, Á. & Győrffy, B. Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma. R. Soc. Open Sci. 5, 181006 (2018). source

      The Results section on prognostic biomarker candidates reports that high expression of some genes was associated with improved survival, but the passages found do not identify PROX1 among them. Searches for PROX1 and for PROX1 expression or amplification in relation to survival found no passage addressing the claimed association. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Findingcitation

    PROX1 expression is lower in tumor samples than in normal tissues in patients with HCC.

    “we assessed whether PROX1 is dysregulated in patients with HCC and found lower expression in tumor samples than in normal tissues24”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Chaisaingmongkol, J. et al. Common molecular subtypes among asian hepatocellular carcinoma and cholangiocarcinoma. Cancer Cell 32, 57–70 (2017). source

      The Results section discusses PLK1 and ECT2 expression in HCC, and the STAR METHODS section describes paired tumor and nontumor expression measurements. Neither reports a PROX1 comparison. Searches for “PROX1” and for lower expression in HCC tumors than normal tissue found no passage addressing the claimed result; page numbers were not available in our copy. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 16
  • May combine two claims. 45
  • The quote only partly states this claim. 3

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MYT1L is expressed lifelong.

    “MYT1L is expressed lifelong”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Hu, J. et al. Neutralization of terminal differentiation in gliomagenesis. Proc. Natl Acad. Sci. USA 110, 14520–14527 (2013). source

      The Results report MYT1L expression in glioblastoma samples and examine its function in neural stem cells, but do not describe expression across the lifespan. Searches for lifelong expression and expression throughout development and adulthood found no passage establishing the claim. Page numbers were not available in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [14] Weigel, B. et al. MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention. Mol. Psychiatry 28, 2122–2135 (2023). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    14 candidates were reported to promote the predicted cell fate.

    “14 were reported to promote the predicted cell fate, including the neuronal safeguard MYT1L12”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Mall, M. et al. Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates. Nature 544, 245–249 (2017). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Both tumor-promoting and suppressor roles have been reported for PROX1 in liver cancer models.

    “but both tumor-promoting and suppressor roles have been reported in liver cancer models22,23”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [22] Liu, Y. et al. PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability. Hepatology 58, 692–705 (2013). source
    • cites [23] Shimoda, M. et al. A homeobox protein, Prox1, is involved in the differentiation, proliferation, and prognosis in hepatocellular carcinoma. Clin. Cancer Res. 12, 6005–6011 (2006). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MYT1L loss of function is associated with mental disorders and brain cancer.

    “its loss of function is associated with mental disorders and brain cancer13,14.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Hu, J. et al. Neutralization of terminal differentiation in gliomagenesis. Proc. Natl Acad. Sci. USA 110, 14520–14527 (2013). source

      The Results (page not available in our copy) report MYT1L deletion or reduced expression in glioblastoma samples and show that MYT1L knockdown induced tumors in a mouse model, supporting the brain-cancer part. The passage linking genomic alterations to neurodevelopmental and neuropsychiatric disorders concerns A2BP1, not MYT1L; our copy does not establish the claimed MYT1L–mental-disorder association. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [14] Weigel, B. et al. MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention. Mol. Psychiatry 28, 2122–2135 (2023). source

      The Discussion (page unavailable) links MYT1L deficiency to neurodevelopmental and neuropsychiatric phenotypes, including ASD and schizophrenia. Our copy does not support the additional association with brain cancer; a search for cancer found no relevant passage. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Median survival almost doubled in the paper's models and increased by 2-3 weeks, double the increase induced by sorafenib in comparable models.

    “Strikingly, median survival almost doubled in our models and increased by 2–3 weeks, double the increase induced by the kinase inhibitor sorafenib, a standard of care in unresectable HCC, in comparable models62.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Rudalska, R. et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med. 20, 1138–1146 (2014). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The repressor Kmg inhibits somatic lineage genes in Drosophila melanogaster germ cells.

    “For example, the repressor Kmg inhibits somatic lineage genes in Drosophila melanogaster germ cells57.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [57] Kim, J. et al. Blocking promiscuous activation at cryptic promoters directs cell type-specific gene expression. Science 356, 717–721 (2017). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PROX1 can function as a master regulator of lymphatic endothelial cells.

    “Notably, PROX1 can function as an activator to promote neurogenesis in the brain39,40, or as a master regulator of lymphatic endothelial cells41,42.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [41] Petrova, T. V. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J. 21, 4593–4599 (2002). source
    • cites [42] Wigle, J. T. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 21, 1505–1513 (2002). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PROX1 can function as an activator to promote neurogenesis in the brain.

    “Notably, PROX1 can function as an activator to promote neurogenesis in the brain39,40, or as a master regulator of lymphatic endothelial cells41,42.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [39] Karalay, Ö. et al. Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis. Proc. Natl Acad. Sci. USA 108, 5807–5812 (2011). source
    • cites [40] Lavado, A., Lagutin, O. V., Chow, L. M. L., Baker, S. J. & Oliver, G. Prox1 is required for granule cell maturation and intermediate progenitor maintenance during brain neurogenesis. PLoS Biol. 8, e1000460 (2010). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Loss of master regulators, such as Pax5 in B cells, can cause plasticity and even cancer.

    “Their loss, for example, Pax5 in B cells, can cause plasticity and even cancer6,7,55,56.”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [6] Cobaleda, C., Jochum, W. & Busslinger, M. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 449, 473–477 (2007). source
    • cites [7] Krah, N. M. et al. The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. eLife 4, e07125 (2015). source

      The Abstract and Results report that loss of the acinar differentiation regulator PTF1A promotes cellular reprogramming and increases susceptibility to KRAS-driven pancreatic cancer. The paper does not address the sentence’s specific example of Pax5 loss in B cells; that part is not supported by this source. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [55] Li, P. et al. Reprogramming of T cells to natural killer-like cells upon Bcl11b deletion. Science 329, 85–89 (2010). source

      The paper reports that deleting the transcription factor Bcl11b caused T cells to acquire NK-cell properties, supporting the general point that loss of a lineage regulator can cause plasticity. It does not report Pax5 loss in B cells or cancer caused by regulator loss. Its tumor finding is instead that the reprogrammed cells killed tumor cells and prevented metastasis (Abstract; no page given in our copy). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [56] Nechanitzky, R. et al. Transcription factor EBF1 is essential for the maintenance of B cell identity and prevention of alternative fates in committed cells. Nat. Immunol. 14, 867–875 (2013). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The neuron-specific repressor MYT1L suppresses non-neuronal genes in neurons.

    “Similarly, the neuron-specific repressor MYT1L suppresses non-neuronal genes in neurons11,12.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [11] Lee, Q. Y. et al. Pro-neuronal activity of Myod1 due to promiscuous binding to neuronal genes. Nat. Cell Biol. 22, 401–411 (2020). source
    • cites [12] Mall, M. et al. Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates. Nature 544, 245–249 (2017). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In colorectal cancer, PROX1 has been described as suppressing lineage plasticity by repressing nonintestinal genes.

    “Interestingly, in the context of colorectal cancer, PROX1 has been recently described as suppressing lineage plasticity by repressing nonintestinal genes64, supporting the notion that it can prevent cell fate plasticity and cancer.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [64] Moorman, A. R. et al. Progressive plasticity during colorectal cancer metastasis. Nature 637, 947–954 (2025). source

  • May combine two claims.

    Findingown data

    We shortlisted 59 candidates, of which 50 have reported repressor or dual activator/repressor function.

    “We shortlisted 59 candidates, of which 50 have reported repressor or dual activator/repressor function”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The top hepatocyte candidate, PROX1, exhibited hepatocyte-specific expression and bound many nonhepatocyte genes.

    “The top hepatocyte candidate, PROX1, exhibited hepatocyte-specific expression and bound many nonhepatocyte genes, based on motif enrichment and cleavage under targets and release using nuclease (CUT&RUN) binding”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Prox1 OE cells downregulated the MEF fate more efficiently and displayed fewer alternative cell identities.

    “These cells also downregulated the MEF fate more efficiently and displayed fewer alternative cell identities”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The repressor fusion improved hepatocyte fate induction similarly to full-length PROX1, while the activator fusion had a dominant negative effect, impairing conversion.

    “The repressor fusion improved hepatocyte fate induction similarly to full-length PROX1, while the activator fusion had a dominant negative effect, impairing conversion”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Prox1 OE increased hepatocyte identity, and the number of successfully reprogrammed hepatocytes was greater than sevenfold.

    “Prox1 OE increased hepatocyte identity, and the number of successfully reprogrammed hepatocytes was greater than sevenfold.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RNA-seq confirmed that genetic Prox1−/− deletion decreased liver marker expression during hepatocyte reprogramming and increased levels of alternative fate markers such as neuronal Map2 and myocyte Myh9.

    “RNA-seq confirmed that genetic Prox1−/− deletion decreased liver marker expression during hepatocyte reprogramming and increased levels of alternative fate markers such as neuronal Map2 and myocyte Myh9”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Prox1 levels are lower in transformed cells compared to hepatocytes, coinciding with decreased hepatocyte identity.

    “We found lower Prox1 levels in transformed cells compared to hepatocytes, coinciding with decreased hepatocyte identity”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In hepatocyte reprogramming, the EnR fusion triggered a similar gene expression response as full-length PROX1, inducing hepatocyte genes like Alb and repressing nonhepatocyte markers such as Krt19, while the activator fusion had the opposite effect.

    “In hepatocyte reprogramming, the EnR fusion triggered a similar gene expression response as full-length PROX1, inducing hepatocyte genes like Alb and repressing nonhepatocyte markers such as Krt19, while the activator fusion had the opposite effect”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All resulting tumors in constitutive Prox1 OE were GFP-negative, indicating selection against Prox1 OE.

    “and all resulting tumors were GFP-negative, indicating selection against Prox1 OE”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Prox1 expression and hepatocyte identity sharply decreased following DDC-induced injury and recovered during regeneration.

    “we found that Prox1 expression and hepatocyte identity sharply decreased following 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced injury and recovered during regeneration”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MYC and MYC targets were downregulated upon PROX1 OE, coinciding with increased apoptosis signatures.

    “RNA-seq and gene regulatory network analysis confirmed that MYC and MYC targets were downregulated upon PROX1 OE, coinciding with increased apoptosis signatures”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The repressor fusion decreased the fraction of reprogrammed cells that expressed neuronal or myocyte markers, while the activator fusion increased them.

    “The repressor fusion decreased the fraction of reprogrammed cells that expressed neuronal or myocyte markers, while the activator fusion increased them”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Conditional Prox1 deletion resulted in greater than sevenfold decreased TJP1-positive hepatocyte-like cells and lower albumin secretion per cell.

    “conditional Prox1 deletion resulted in greater than sevenfold decreased TJP1-positive hepatocyte-like cells and lower albumin secretion per cell”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upon Prox1 OE, 111,411 differentially accessible peaks were found, of which 85,140 (76.4%) were closed.

    “We found 111,411 differentially accessible peaks (adjusted P < 0.05) upon Prox1 OE, of which 85,140 (76.4%) were closed”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The activator fusion reduced neuronal cell induction but enhanced myocyte induction, increasing the fraction of desmin-positive cells in both conversions relative to DBD.

    “the activator fusion reduced neuronal cell induction but enhanced myocyte induction, increasing the fraction of desmin-positive cells in both conversions relative to DBD”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    MYT1L inhibited myocyte and hepatocyte reprogramming while promoting neuronal conversion.

    “MYT1L had similar effects, inhibiting myocyte and hepatocyte reprogramming while promoting neuronal conversion”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cluster 1 (hepatocyte cluster) contained 3,629 upregulated genes with increased promoter accessibility and was enriched for hepatocyte identity genes but also contained cholangiocyte and oligodendrocyte signature genes.

    “Cluster 1 (hepatocyte cluster) contained 3,629 upregulated genes with increased promoter accessibility and was enriched for hepatocyte identity genes but also contained cholangiocyte and oligodendrocyte signature genes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    PROX1 binding caused decreased chromatin accessibility and repression of alternative fate master regulators.

    “Third, PROX1 binding caused decreased chromatin accessibility and repression of alternative fate master regulators.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Except for PROX1, all downstream TFs were predicted to act as gene activators, and their target genes were enriched in the repressed alternative fate cluster.

    “Except for PROX1, all downstream TFs were predicted to act as gene activators, and their target genes were enriched in the repressed alternative fate cluster”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On day 2, most expression changes were explained by PROX1, while from day 7, direct PROX1 targets PRRX1 and EBF2 regulated most effects.

    “On day 2, most expression changes were explained by PROX1, while from day 7, we predicted that direct PROX1 targets PRRX1 and EBF2 regulated most effects”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cluster 2 (alternative fate cluster) included 3,264 downregulated genes with reduced promoter accessibility and contained eight alternative fate marker genes.

    “Cluster 2 (alternative fate cluster) included 3,264 downregulated genes with reduced promoter accessibility and contained eight alternative fate marker genes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The hepatocyte cluster was enriched for 4-in-1 and depleted for PROX1 targets, while the alternative fate cluster was enriched for direct PROX1 targets.

    “The hepatocyte cluster was enriched for 4-in-1 and depleted for PROX1 targets, while the alternative fate cluster was enriched for direct PROX1 targets”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Prox1 knockdown in HCC mice caused downregulation of hepatocyte markers (e.g., Alb and Ttr) and upregulation of cholangiocyte markers (e.g., Krt19 and Sox9).

    “Prox1 knockdown in HCC caused downregulation of hepatocyte markers (for example, Alb and Ttr) and upregulation of cholangiocyte markers (for example, Krt19 and Sox9)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CRISPR-mediated Prox1 knockout in the Myc/Trp53 HCC mouse model increased tumor numbers greater than twofold and decreased median survival by ~10 days.

    “This increased tumor numbers greater than twofold and decreased median survival by ~10 days”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Analysis of 1,296 TFs identified 27 candidates across 18 cell types, with >50% linked to promoting their predicted cell fates.

    “Analysis of 1,296 TFs identified 27 candidates across 18 cell types, with >50% linked to promoting their predicted cell fates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Prox1 overexpression induced a CCA-to-HCC shift, with fewer glandular structures, lower KRT19 expression and higher HNF4 levels.

    “Strikingly, Prox1 OE induced a CCA-to-HCC shift, with fewer glandular structures, lower KRT19 expression and higher HNF4 levels (Fig. 7c,d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Prrx1 and Pparg were bound and repressed by PROX1.

    “We verified that Prrx1 and Pparg were bound and repressed by PROX1”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Prox1 knockdown with shRNA constructs coupled to a GFP reporter led to a tenfold increase in tumor nodules after 2 weeks without affecting tumor number and survival at the endpoint.

    “This led to a tenfold increase in tumor nodules after 2 weeks without affecting tumor number and survival at the endpoint”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    shRNA-mediated depletion of Prrx1 or Pparg increased hepatocyte conversion only in the absence of Prox1 OE, indicating that both act downstream of PROX1.

    “shRNA-mediated depletion of Prrx1 or Pparg increased hepatocyte conversion only in the absence of Prox1 OE, indicating that both act downstream of PROX1”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Inducing Prox1 overexpression after 21 days of HDTVI-mediated tumor formation decreased glandular structures and reduced cholangiocyte marker expression (KRT19 and SOX9).

    “Inducing Prox1 OE after 21 days of HDTVI-mediated tumor formation also decreased glandular structures and reduced cholangiocyte marker expression (KRT19 and SOX9; Extended Data Fig. 10g–j).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PROX1 interacted with the repressive NuRD complex in the liver but not in the brain.

    “Conversely, in hepatocytes, corepressor interactions are reported43–45, and we found that PROX1 interacted with the repressive NuRD complex in the liver but not in the brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Prox1 knockdown induced a shift from HCC toward CCA, forming glandular tumor structures expressing KRT19 and decreased HNF4 levels.

    “Prox1 knockdown induced a shift from HCC toward CCA, forming glandular tumor structures expressing KRT19 and decreased HNF4 levels”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PROX1 promotes liver development in mice.

    “In mice, PROX1 promotes liver development21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Seth, A. et al. Prox1 ablation in hepatic progenitors causes defective hepatocyte specification and increases biliary cell commitment. Development 141, 538–547 (2014). source

  • May combine two claims.

    Interpretationown data

    Cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and prevent disease.

    “support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.”
    • Also stated in: § Main · plain
      “This supports a model where cell-type-specific safeguard repressors actively suppress unwanted plasticity to induce and maintain cell identity and block tumorigenesis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The prevalence of safeguard repressors across lineages and their role in cancer is unclear.
    • The authors state this as an assumption: The three features used to define safeguard repressors (cell-type-specific lifelong expression, binding/repressing alternative fate genes, promoting/maintaining cell identity) are sufficient to identify safeguard repressors.

  • The quote only partly states this claim.

    Interpretationown data

    PROX1 is a hepatocyte-specific safeguard repressor.

    “Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard”
    • Also stated in: § Main · plain
      “This supports a model where cell-type-specific safeguard repressors actively suppress unwanted plasticity to induce and maintain cell identity and block tumorigenesis.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The three features used to define safeguard repressors (cell-type-specific lifelong expression, binding/repressing alternative fate genes, promoting/maintaining cell identity) are sufficient to identify safeguard repressors.

  • The quote only partly states this claim.

    Interpretationown data

    PROX1 enhanced hepatocyte identity by direct repression of alternative fate master regulators.

    “This shows that PROX1 represses nonhepatocyte fate genes to promote hepatocyte identity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Safeguard repressors such as PROX1 and MYT1L promote a specific cell fate and might redirect the cell fates induced by neuronal and muscle master regulators.

    “This suggests that safeguard repressors such as PROX1 and MYT1L promote a specific cell fate and might redirect the cell fates induced by neuronal and muscle master regulators.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PROX1 can directly repress nonhepatic gene signatures, potentially activated by 4-in-1, to promote the desired hepatocyte fate.

    “This suggests that PROX1 can directly repress nonhepatic gene signatures, potentially activated by 4-in-1, to promote the desired hepatocyte fate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PROX1 functions as a tumor suppressor by impeding tumor initiation and progression in distinct liver cancer mouse models.

    “This demonstrates that PROX1 functions as a tumor suppressor by impeding tumor initiation and progression in distinct liver cancer mouse models.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PROX1 primarily closes chromatin in liver cancer cells and reduces their proliferation by gene repression.

    “This shows that PROX1 primarily closes chromatin in liver cancer cells and reduces their proliferation by gene repression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PROX1 is sufficient and necessary for efficient hepatocyte fate induction by repressing alternative fates.

    “indicating that PROX1 is sufficient and necessary for efficient hepatocyte fate induction by repressing alternative fates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PROX1 represses alternative fates to promote hepatocyte fate.

    “showing that PROX1 represses alternative fates to promote hepatocyte fate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PROX1 primarily closes chromatin and reduces the expression of directly bound target gene promoters.

    “showing that PROX1 primarily closes chromatin and reduces the expression of directly bound target gene promoters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PROX1 can maintain hepatocyte cell identity and prevent liver disease in vivo, with lower levels permitting plasticity and higher levels reducing transformation and transdifferentiation.

    “This suggests that PROX1 can maintain hepatocyte cell identity and prevent liver disease in vivo, with lower levels permitting plasticity and higher levels reducing transformation and transdifferentiation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: PROX1 expression differs in samples of patients with human liver cancer.

  • May combine two claims.

    Interpretationreasoning

    PROX1 could regulate liver cancer plasticity and HCC versus CCA fate.

    “suggesting that PROX1 could regulate liver cancer plasticity and HCC versus CCA fate.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The factors regulating the transformation of hepatocytes to HCC versus CCA are largely unknown.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Prox1 overexpression in tumor cells induced migratory and metastatic potential upon transplantation in prior studies.

    “This contrasts studies where Prox1 OE in tumor cells induced migratory and metastatic potential upon transplantation22,63.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Liu, Y. et al. PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability. Hepatology 58, 692–705 (2013). source
    • cites [63] Liu, Y. et al. PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation. Oncogene 34, 5524–5535 (2015). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The investigators were blinded to the microscopy analysis and quantification.

    “The investigators were blinded to the microscopy analysis and quantification.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Interpretationcitation

    PROX1 can prevent cell fate plasticity and cancer.

    “Interestingly, in the context of colorectal cancer, PROX1 has been recently described as suppressing lineage plasticity by repressing nonintestinal genes64, supporting the notion that it can prevent cell fate plasticity and cancer.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Apart from the microscopy analysis and quantification, no blinding and randomization were performed.

    “Otherwise, no blinding and randomization were performed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No statistical methods were used to predetermine the sample size for the experiments.

    “No statistical methods were used to predetermine the sample size for the experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Animals for primary cultures and in vivo experiments were selected randomly before the indicated treatments.

    “Animals for primary cultures and in vivo experiments were selected randomly before indicated treatments.”
    Quote in the paperNot a substantial claim
62 of 62

  • The paper relies on this without support.

    The prevalence of safeguard repressors across lineages and their role in cancer is unclear.

    “The prevalence of such safeguard repressors across lineages and their role in cancer is unclear.”

  • The paper relies on this without support.

    The factors regulating the transformation of hepatocytes to HCC versus CCA are largely unknown.

    “However, the factors regulating the transformation of hepatocytes to HCC versus CCA are largely unknown.”

  • The authors state this as an assumption.

    The three features used to define safeguard repressors (cell-type-specific lifelong expression, binding/repressing alternative fate genes, promoting/maintaining cell identity) are sufficient to identify safeguard repressors.

    “To identify safeguard repressors, we defined the following three features: (1) cell-type-specific and lifelong expression, (2) binding and repressing alternative fate genes and (3) promoting and maintaining cell identity.”

  • The paper relies on this without support.

    PROX1 expression differs in samples of patients with human liver cancer.

    “In line with PROX1 expression differences in samples of patients with human liver cancer, manipulating PROX1 in mouse liver cancer models could switch the transformation trajectory of hepatocytes between CCA and HCC.”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Survival gain exceeds the stated two-to-three-week range

    Minor

    The Discussion describes the median-survival increase in the models as two to three weeks, but the reported increase from 29 to 64 days is 35 days, or five weeks.

  • Reported HDTVI group sizes fall below the stated minimum

    Minor

    The Methods state that every HDTVI experimental group had at least five mice, but the Kras/Trp53 survival experiment reports four mice per group.

  • MYC-driven single-cell dataset has conflicting reference numbers

    Minor

    The Fig. 2 legend cites reference 35 for the MYC-induced HCC single-cell data, whereas the Methods identify the Myc-driven liver tumor dataset as reference 34.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Garcia-Bellido, A. in Ciba Foundation Symposium 29—Cell Patterning (eds Porter, R. & Rivers, J.) Ch. 8 (Ciba Foundation, 1975).

Cited by

Sorted by citations

Related

Authors
Lim, B., Kamal, A., Gomez Ramos, B., Adrian Segarra, J. M., Ibarra, I. L., Dignas, L., Kindinger, T., Volz, K., Rahbari, M., Rahbari, N., Poisel, E., Kafetzopoulou, K., Böse, L., Breinig, M., Heide, D., Gallage, S., Barragan Avila, J. E., Wiethoff, H., Berest, I., Schnabellehner, S., Schneider, M., Becker, J., Helm, D., Grimm, D., Mäkinen, T., Tschaharganeh, D. F., Heikenwalder, M., Zaugg, J. B., & Mall, M.
Affiliations
  • German Cancer Research Center (DE)
  • University of Basel (CH)
  • Heidelberg University (DE)
  • Universität Ulm (DE)
  • University Hospital Heidelberg (DE)
  • Uppsala University (SE)
Corresponding author
  • Zaugg, Judith B.
  • Mall, Moritz
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2025-02-13
Volume
57
Issue
3
Pages
668-679
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-025-02081-w
PMC
PMC11906372
OpenAlex
W4407550321
Semantic Scholar
0af52c4ca0b5a05c3217ac280002ccfd0a9e92d3
Cited by
17
References
103
Citations by year
2026: 8 · 2025: 9
FWCI
8.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft (SFB TR 179)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
Prox1, cell fate plasticity, hepatocarcinogenesis, hepatocyte regeneration, hepatocellular carcinoma, cholangiocarcinoma, transdifferentiation, lineage identity, transcriptional repression
MeSH terms
Cell Plasticity, Prospero-Related Homeobox 1 Protein, Animals, Bile Duct Neoplasms, Cell Differentiation, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Gene Expression Regulation, Neoplastic, Cholangiocarcinoma, Homeodomain Proteins, Cell Lineage, Hepatocytes, Tumor Suppressor Proteins, Mice, Cell Transdifferentiation, Carcinogenesis

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 2026-10-22.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-22.

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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