{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T20:11:55Z","timestamp":1789848715238,"version":"4.0.1"},"reference-count":51,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,10]],"date-time":"2020-11-10T00:00:00Z","timestamp":1604966400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,11,10]],"date-time":"2020-11-10T00:00:00Z","timestamp":1604966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"NIAAA\/NIH","award":["P50AA011999"],"award-info":[{"award-number":["P50AA011999"]}]},{"name":"NIAAA\/NIH","award":["R24 AA012885"],"award-info":[{"award-number":["R24 AA012885"]}]},{"name":"HHS-NIH","award":["U01AA027681"],"award-info":[{"award-number":["U01AA027681"]}]},{"name":"VA Merit Review","award":["I01 BX001991"],"award-info":[{"award-number":["I01 BX001991"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Prominin 1 (PROM1) is one of a few clinically relevant progenitor markers in human alcoholic hepatitis (AH) and hepatocellular carcinoma (HCC), and mouse liver tumor initiating stem cell-like cells (TICs). However, the origin, fate and functions of PROM1<jats:sup>+<\/jats:sup>\u2009cells in AH and HCC are unknown. Here we show by genetic lineage tracing that PROM1<jats:sup>+<\/jats:sup>\u2009cells are derived in part from hepatocytes in AH and become tumor cells in mice with diethyl nitrosamine (DEN)-initiated, Western alcohol diet-promoted liver tumorigenesis. Our RNA sequencing analysis of mouse PROM1<jats:sup>+<\/jats:sup>\u2009cells, reveals transcriptomic landscapes indicative of their identities as ductular reaction progenitors (DRPs) and TICs. Indeed, single-cell RNA sequencing reveals two subpopulations of <jats:italic>Prom1<\/jats:italic><jats:sup>+<\/jats:sup>\u2009<jats:italic>Afp<\/jats:italic><jats:sup>\u2013<\/jats:sup> DRPs and <jats:italic>Prom1<\/jats:italic><jats:sup>+<\/jats:sup>\u2009<jats:italic>Afp<\/jats:italic><jats:sup>+<\/jats:sup>\u2009TICs in the DEN-WAD model. Integrated bioinformatic analysis identifies Discodin Domain Receptor 1 (<jats:italic>DDR1<\/jats:italic>) as a uniquely upregulated and patient-relevant gene in PROM1<jats:sup>+<\/jats:sup>\u2009cells in AH and HCC. Translational relevance of <jats:italic>DDR1<\/jats:italic> is supported by its marked elevation in HCC which is inversely associated with patient survival. Further, knockdown of <jats:italic>Ddr1<\/jats:italic> suppresses the growth of TICs and TIC-derived tumor growth in mice. These results suggest the importance of PROM1<jats:sup>+<\/jats:sup>\u2009cells in the evolution of liver cancer and DDR1 as a potential driver of this process.<\/jats:p>","DOI":"10.1038\/s41598-020-76458-8","type":"journal-article","created":{"date-parts":[[2020,11,10]],"date-time":"2020-11-10T11:02:41Z","timestamp":1605006161000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Fate and functional roles of Prominin 1+ cells in liver injury and cancer"],"prefix":"10.1038","volume":"10","author":[{"given":"Raymond","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Balog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidekazu","family":"Tsukamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,10]]},"reference":[{"key":"76458_CR1","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.stem.2014.04.010","volume":"14","author":"A Miyajima","year":"2014","unstructured":"Miyajima, A., Tanaka, M. & Itoh, T. Stem\/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14, 561\u2013574. https:\/\/doi.org\/10.1016\/j.stem.2014.04.010 (2014).","journal-title":"Cell Stem Cell"},{"key":"76458_CR2","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1053\/j.gastro.2015.08.004","volume":"149","author":"GK Michalopoulos","year":"2015","unstructured":"Michalopoulos, G. K. & Khan, Z. Liver stem cells: experimental findings and implications for human liver disease. Gastroenterology 149, 876\u2013882. https:\/\/doi.org\/10.1053\/j.gastro.2015.08.004 (2015).","journal-title":"Gastroenterology"},{"key":"76458_CR3","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.stem.2014.09.008","volume":"15","author":"BD Tarlow","year":"2014","unstructured":"Tarlow, B. D. et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15, 605\u2013618. https:\/\/doi.org\/10.1016\/j.stem.2014.09.008 (2014).","journal-title":"Cell Stem Cell"},{"key":"76458_CR4","doi-asserted-by":"publisher","first-page":"2832","DOI":"10.1172\/JCI65859","volume":"123","author":"CL Chen","year":"2013","unstructured":"Chen, C. L. et al. Reciprocal regulation by TLR4 and TGF-\u03b2 in tumor-initiating stem-like cells. J. Clin. Invest. 123, 2832\u20132849. https:\/\/doi.org\/10.1172\/JCI65859 (2013).","journal-title":"J. Clin. Invest."},{"key":"76458_CR5","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1016\/j.stem.2010.11.010","volume":"7","author":"S Ma","year":"2010","unstructured":"Ma, S. et al. miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 7, 694\u2013707. https:\/\/doi.org\/10.1016\/j.stem.2010.11.010 (2010).","journal-title":"Cell Stem Cell"},{"key":"76458_CR6","doi-asserted-by":"publisher","first-page":"47431","DOI":"10.18632\/oncotarget.10164","volume":"7","author":"Q Zhao","year":"2016","unstructured":"Zhao, Q. et al. Prognostic value of the expression of cancer stem cell-related markers CD133 and CD44 in hepatocellular carcinoma: from patients to patient-derived tumor xenograft models. Oncotarget 7, 47431\u201347443. https:\/\/doi.org\/10.18632\/oncotarget.10164 (2016).","journal-title":"Oncotarget"},{"key":"76458_CR7","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1002\/hep.25614","volume":"55","author":"P Sancho-Bru","year":"2012","unstructured":"Sancho-Bru, P. et al. Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis. Hepatology 55, 1931\u20131941. https:\/\/doi.org\/10.1002\/hep.25614 (2012).","journal-title":"Hepatology"},{"key":"76458_CR8","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.15034","author":"K Kamimoto","year":"2016","unstructured":"Kamimoto, K. et al. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling. Elife. https:\/\/doi.org\/10.7554\/eLife.15034 (2016).","journal-title":"Elife."},{"key":"76458_CR9","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1016\/j.cell.2016.07.045","volume":"166","author":"L Zhu","year":"2016","unstructured":"Zhu, L. et al. Multi-organ mapping of cancer risk. Cell 166, 1132\u20131146.e1137. https:\/\/doi.org\/10.1016\/j.cell.2016.07.045 (2016).","journal-title":"Cell"},{"key":"76458_CR10","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1172\/JCI77995","volume":"125","author":"X Mu","year":"2015","unstructured":"Mu, X. et al. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor\/biliary compartment. J. Clin. Invest. 125, 3891\u20133903. https:\/\/doi.org\/10.1172\/JCI77995 (2015).","journal-title":"J. Clin. Invest."},{"key":"76458_CR11","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41572-018-0014-7","volume":"4","author":"HK Seitz","year":"2018","unstructured":"Seitz, H. K. et al. Alcoholic liver disease. Nat. Rev. Dis. Primers 4, 16. https:\/\/doi.org\/10.1038\/s41572-018-0014-7 (2018).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"76458_CR12","doi-asserted-by":"publisher","first-page":"2758","DOI":"10.1056\/NEJMra0805786","volume":"360","author":"MR Lucey","year":"2009","unstructured":"Lucey, M. R., Mathurin, P. & Morgan, T. R. Alcoholic hepatitis. N. Engl. J. Med. 360, 2758\u20132769. https:\/\/doi.org\/10.1056\/NEJMra0805786 (2009).","journal-title":"N. Engl. J. Med."},{"key":"76458_CR13","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1136\/gutjnl-2014-308410","volume":"64","author":"L Dubuquoy","year":"2015","unstructured":"Dubuquoy, L. et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut 64, 1949\u20131960. https:\/\/doi.org\/10.1136\/gutjnl-2014-308410 (2015).","journal-title":"Gut"},{"key":"76458_CR14","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1002\/hep.27383","volume":"61","author":"R Lazaro","year":"2015","unstructured":"Lazaro, R. et al. Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice. Hepatology 61, 129\u2013140. https:\/\/doi.org\/10.1002\/hep.27383 (2015).","journal-title":"Hepatology"},{"key":"76458_CR15","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.cld.2012.08.011","volume":"16","author":"P Grewal","year":"2012","unstructured":"Grewal, P. & Viswanathen, V. A. Liver cancer and alcohol. Clin. Liver Dis. 16, 839\u2013850. https:\/\/doi.org\/10.1016\/j.cld.2012.08.011 (2012).","journal-title":"Clin. Liver Dis."},{"key":"76458_CR16","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1073\/pnas.0807390106","volume":"106","author":"K Machida","year":"2009","unstructured":"Machida, K. et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc. Natl. Acad. Sci U S A 106, 1548\u20131553. https:\/\/doi.org\/10.1073\/pnas.0807390106 (2009).","journal-title":"Proc. Natl. Acad. Sci U S A"},{"key":"76458_CR17","doi-asserted-by":"publisher","first-page":"4850","DOI":"10.1172\/JCI59261","volume":"121","author":"Y Malato","year":"2011","unstructured":"Malato, Y. et al. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J. Clin. Invest. 121, 4850\u20134860. https:\/\/doi.org\/10.1172\/JCI59261 (2011).","journal-title":"J. Clin. Invest."},{"key":"76458_CR18","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1002\/hep.29778","volume":"68","author":"H Zheng","year":"2018","unstructured":"Zheng, H. et al. Single-cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma. Hepatology 68, 127\u2013140. https:\/\/doi.org\/10.1002\/hep.29778 (2018).","journal-title":"Hepatology"},{"key":"76458_CR19","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/nature07589","volume":"457","author":"L Zhu","year":"2009","unstructured":"Zhu, L. et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603\u2013607. https:\/\/doi.org\/10.1038\/nature07589 (2009).","journal-title":"Nature"},{"key":"76458_CR20","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.cell.2013.09.031","volume":"155","author":"G He","year":"2013","unstructured":"He, G. et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155, 384\u2013396. https:\/\/doi.org\/10.1016\/j.cell.2013.09.031 (2013).","journal-title":"Cell"},{"issue":"1","key":"76458_CR21","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.1038\/s41467-019-10739-3","volume":"10","author":"R Zhu","year":"2019","unstructured":"Zhu, R. et al. TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling. Nat. Commun. 10(1), 2863. https:\/\/doi.org\/10.1038\/s41467-019-10739-3 (2019).","journal-title":"Nat. Commun."},{"issue":"12","key":"76458_CR22","doi-asserted-by":"publisher","first-page":"3504","DOI":"10.1016\/j.celrep.2018.11.069","volume":"25","author":"JD Barros-Silva","year":"2018","unstructured":"Barros-Silva, J. D. et al. Single-cell analysis identifies LY6D as a marker linking castration-resistant prostate luminal cells to prostate progenitors and cancer. Cell Rep. 25(12), 3504\u20133518.e6. https:\/\/doi.org\/10.1016\/j.celrep.2018.11.069 (2018).","journal-title":"Cell Rep."},{"key":"76458_CR23","doi-asserted-by":"publisher","first-page":"819","DOI":"10.3389\/fimmu.2019.00819","volume":"10","author":"G Upadhyay","year":"2019","unstructured":"Upadhyay, G. Emerging role of lymphocyte Antigen-6 family of genes in cancer and immune cells. Front. Immunol. 10, 819. https:\/\/doi.org\/10.3389\/fimmu.2019.00819 (2019).","journal-title":"Front. Immunol."},{"key":"76458_CR24","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1002\/hep.29645","volume":"67","author":"E Khanova","year":"2018","unstructured":"Khanova, E. et al. Pyroptosis by caspase11\/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 67, 1737\u20131753. https:\/\/doi.org\/10.1002\/hep.29645 (2018).","journal-title":"Hepatology"},{"key":"76458_CR25","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/s1097-2765(00)80003-9","volume":"1","author":"W Vogel","year":"1997","unstructured":"Vogel, W., Gish, G. D., Alves, F. & Pawson, T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol. Cell. 1, 13\u201323. https:\/\/doi.org\/10.1016\/s1097-2765(00)80003-9 (1997).","journal-title":"Mol Cell"},{"key":"76458_CR26","doi-asserted-by":"publisher","first-page":"45895","DOI":"10.1038\/srep45895","volume":"7","author":"JC Yang","year":"2017","unstructured":"Yang, J. C. et al. TM4SF1 promotes metastasis of pancreatic cancer via regulating the expression of DDR1. Sci. Rep. 7, 45895. https:\/\/doi.org\/10.1038\/srep45895 (2017).","journal-title":"Sci. Rep."},{"issue":"6","key":"76458_CR27","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1016\/j.cell.2007.11.025","volume":"131","author":"K Rikova","year":"2007","unstructured":"Rikova, K. et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6), 1190\u20131203. https:\/\/doi.org\/10.1016\/j.cell.2007.11.025 (2007).","journal-title":"Cell"},{"issue":"11","key":"76458_CR28","doi-asserted-by":"publisher","first-page":"19539","DOI":"10.1002\/jcp.28552","volume":"234","author":"R Azizi","year":"2019","unstructured":"Azizi, R., Salemi, Z., Fallahian, F. & Aghaei, M. Inhibition of discoidin domain receptor 1 reduces epithelial-mesenchymal transition and induce cell-cycle arrest and apoptosis in prostate cancer cell lines. J. Cell Physiol. 234(11), 19539\u201319552. https:\/\/doi.org\/10.1002\/jcp.28552 (2019).","journal-title":"J. Cell Physiol."},{"issue":"4","key":"76458_CR29","doi-asserted-by":"publisher","first-page":"e7918","DOI":"10.15252\/emmm.201707918","volume":"10","author":"M Jeitany","year":"2018","unstructured":"Jeitany, M. et al. Inhibition of DDR1-BCR signaling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer. EMBO Mol. Med. 10(4), e7918. https:\/\/doi.org\/10.15252\/emmm.201707918 (2018).","journal-title":"EMBO Mol. Med."},{"key":"76458_CR30","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1091\/mbc.02-02-0023","volume":"13","author":"X Chen","year":"2002","unstructured":"Chen, X. et al. Gene expression patterns in human liver cancers. Mol. Biol. Cell. 13, 1929\u20131939. https:\/\/doi.org\/10.1091\/mbc.02-02-0023 (2002).","journal-title":"Mol. Biol. Cell."},{"key":"76458_CR31","doi-asserted-by":"publisher","first-page":"85","DOI":"10.2119\/molmed.2008.00110","volume":"15","author":"VR Mas","year":"2009","unstructured":"Mas, V. R. et al. Genes involved in viral carcinogenesis and tumor initiation in hepatitis C virus-induced hepatocellular carcinoma. Mol. Med. 15, 85\u201394. https:\/\/doi.org\/10.2119\/molmed.2008.00110 (2009).","journal-title":"Mol Med"},{"key":"76458_CR32","unstructured":"Goldman, M. et al. (The Cold Spring Harbor Laboratory, BioRxiv, 2018)."},{"key":"76458_CR33","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1016\/j.ccell.2019.04.007","volume":"35","author":"R Xue","year":"2019","unstructured":"Xue, R. et al. Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes. Cancer Cell 35, 932\u2013947.e938. https:\/\/doi.org\/10.1016\/j.ccell.2019.04.007 (2019).","journal-title":"Cancer Cell"},{"key":"76458_CR34","doi-asserted-by":"publisher","first-page":"3034","DOI":"10.1158\/0008-5472.CAN-09-2823","volume":"70","author":"HG Woo","year":"2010","unstructured":"Woo, H. G. et al. Identification of a cholangiocarcinoma-like gene expression trait in hepatocellular carcinoma. Cancer Res 70, 3034\u20133041. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-2823 (2010).","journal-title":"Cancer Res"},{"key":"76458_CR35","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1093\/carcin\/23.3.435","volume":"23","author":"ML Dumble","year":"2002","unstructured":"Dumble, M. L., Croager, E. J., Yeoh, G. C. & Quail, E. A. Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis 23, 435\u2013445 (2002).","journal-title":"Carcinogenesis"},{"key":"76458_CR36","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1002\/hep.27084","volume":"60","author":"BD Tarlow","year":"2014","unstructured":"Tarlow, B. D., Finegold, M. J. & Grompe, M. Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 60, 278\u2013289. https:\/\/doi.org\/10.1002\/hep.27084 (2014).","journal-title":"Hepatology"},{"key":"76458_CR37","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.1053\/j.gastro.2012.08.024","volume":"143","author":"R Espa\u00f1ol-Su\u00f1er","year":"2012","unstructured":"Espa\u00f1ol-Su\u00f1er, R. et al. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143, 1564\u20131575.e1567. https:\/\/doi.org\/10.1053\/j.gastro.2012.08.024 (2012).","journal-title":"Gastroenterology"},{"key":"76458_CR38","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1016\/j.cell.2015.07.026","volume":"162","author":"J Font-Burgada","year":"2015","unstructured":"Font-Burgada, J. et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162, 766\u2013779. https:\/\/doi.org\/10.1016\/j.cell.2015.07.026 (2015).","journal-title":"Cell"},{"key":"76458_CR39","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.stemcr.2019.01.010","volume":"12","author":"X Han","year":"2019","unstructured":"Han, X. et al. Lineage tracing reveals the bipotency of SOX9. Stem Cell Rep. 12, 624\u2013638. https:\/\/doi.org\/10.1016\/j.stemcr.2019.01.010 (2019).","journal-title":"Stem Cell Rep."},{"key":"76458_CR40","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.stem.2018.05.022","volume":"23","author":"X Deng","year":"2018","unstructured":"Deng, X. et al. Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 23, 114\u2013122.e113. https:\/\/doi.org\/10.1016\/j.stem.2018.05.022 (2018).","journal-title":"Cell Stem Cell"},{"key":"76458_CR41","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/nature23015","volume":"547","author":"A Raven","year":"2017","unstructured":"Raven, A. et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547, 350\u2013354. https:\/\/doi.org\/10.1038\/nature23015 (2017).","journal-title":"Nature"},{"key":"76458_CR42","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.canlet.2019.06.002","volume":"459","author":"DW Ho","year":"2019","unstructured":"Ho, D. W. et al. Single-cell transcriptomics reveals the landscape of intra-tumoral heterogeneity and stemness-related subpopulations in liver cancer. Cancer Lett. 459, 176\u2013185. https:\/\/doi.org\/10.1016\/j.canlet.2019.06.002 (2019).","journal-title":"Cancer Lett."},{"issue":"41","key":"76458_CR43","doi-asserted-by":"publisher","first-page":"28115","DOI":"10.1074\/jbc.M109.047258","volume":"284","author":"KN Nejak-Bowen","year":"2009","unstructured":"Nejak-Bowen, K. N., Zeng, G., Tan, X., Cieply, B. & Monga, S. P. Beta-catenin regulates vitamin C biosynthesis and cell survival in murine liver. J. Biol. Chem. 284(41), 28115\u201328127. https:\/\/doi.org\/10.1074\/jbc.M109.047258 (2009).","journal-title":"J. Biol. Chem."},{"issue":"9","key":"76458_CR44","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1158\/2159-8290.CD-19-0061","volume":"9","author":"RC Gimple","year":"2019","unstructured":"Gimple, R. C. et al. Glioma stem cell-specific superenhancer promotes polyunsaturated fatty-acid synthesis to support EGFR signaling. Cancer Discov. 9(9), 1248\u20131267. https:\/\/doi.org\/10.1158\/2159-8290.CD-19-0061 (2019).","journal-title":"Cancer Discov."},{"issue":"5","key":"76458_CR45","doi-asserted-by":"publisher","first-page":"1726","DOI":"10.1002\/hep.30071","volume":"68","author":"R Wu","year":"2018","unstructured":"Wu, R. et al. Baicalein targets GTPase-mediated autophagy to eliminate liver tumor-initiating stem cell-like cells resistant to mTORC1 inhibition. Hepatology 68(5), 1726\u20131740. https:\/\/doi.org\/10.1002\/hep.30071 (2018).","journal-title":"Hepatology"},{"issue":"3","key":"76458_CR46","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/nm.4041","volume":"22","author":"C Ambrogio","year":"2016","unstructured":"Ambrogio, C. et al. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat. Med. 22(3), 270\u2013277. https:\/\/doi.org\/10.1038\/nm.4041 (2016).","journal-title":"Nat. Med."},{"key":"76458_CR47","doi-asserted-by":"publisher","first-page":"2436","DOI":"10.1172\/JCI91786","volume":"128","author":"C Hernandez","year":"2018","unstructured":"Hernandez, C. et al. HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis. J. Clin. Invest. 128, 2436\u20132451. https:\/\/doi.org\/10.1172\/JCI91786 (2018).","journal-title":"J. Clin. Invest."},{"key":"76458_CR48","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1002\/hep4.1026","volume":"1","author":"Y Nakano","year":"2017","unstructured":"Nakano, Y. et al. Identification of a novel alpha-fetoprotein-expressing cell population induced by the Jagged1\/Notch2 signal in murine fibrotic liver. Hepatol. Commun. 1, 215\u2013229. https:\/\/doi.org\/10.1002\/hep4.1026 (2017).","journal-title":"Hepatol. Commun."},{"key":"76458_CR49","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.jhep.2014.09.033","volume":"62","author":"A Page","year":"2015","unstructured":"Page, A. et al. Alcohol directly stimulates epigenetic modifications in hepatic stellate cells. J. Hepatol. 62, 388\u2013397. https:\/\/doi.org\/10.1016\/j.jhep.2014.09.033 (2015).","journal-title":"J. Hepatol."},{"key":"76458_CR50","doi-asserted-by":"publisher","first-page":"14049","DOI":"10.1038\/ncomms14049","volume":"8","author":"GX Zheng","year":"2017","unstructured":"Zheng, G. X. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049. https:\/\/doi.org\/10.1038\/ncomms14049 (2017).","journal-title":"Nat. Commun."},{"key":"76458_CR51","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1093\/biolre\/ioaa007","volume":"102","author":"N Sinha","year":"2020","unstructured":"Sinha, N. et al. Developmental programming: prenatal testosterone-induced epigenetic modulation and its effect on gene expression in sheep ovary\u2020. Biol. Reprod. 102, 1045\u20131054. https:\/\/doi.org\/10.1093\/biolre\/ioaa007 (2020).","journal-title":"Biol. Reprod."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-76458-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-76458-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-76458-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T22:59:07Z","timestamp":1670367547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-76458-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,10]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["76458"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-76458-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,10]]},"assertion":[{"value":"1 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19412"}}