Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling

Nofar Rosenberg, Matthias Van Haele, Tali Lanton, Neta Brashi, Zohar Bromberg, Hanan Adler, Hilla Giladi, Amnon Peled, Daniel S. Goldenberg, Jonathan H. Axelrod, Alina Simerzin, Chofit Chai, Mor Paldor, Auerlia Markezana, Dayana Yaish, Zohar Shemulian, Dvora Gross, Shanny Barnoy, Maytal Gefen, Osher AmranSofie Claerhout, Mirian Fernández-Vaquero, María García-Beccaria, Danijela Heide, Michal Shoshkes-Carmel, Dirk Schmidt Arras, Sharona Elgavish, Yuval Nevo, Hadar Benyamini, Janina E.E. Tirnitz-Parker, Aranzazu Sanchez, Blanca Herrera, Rifaat Safadi, Klaus H. Kaestner, Stefan Rose-John, Tania Roskams, Mathias Heikenwalder*, Eithan Galun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Background & Aims: Primary liver cancers include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA) and combined HCC-CCA tumors (cHCC-CCA). It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA or both types of tumors. Methods: To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor a yellow fluorescent protein (YFP) reporter gene driven by the Foxl1 promoter which is expressed specifically in progenitor cells. These mice (Mdr2-KOFoxl1-CRE;RosaYFP) develop chronic inflammation and HCCs by the age of 14-16 months, followed by cHCC-CCA tumors at the age of 18 months. Results: In this Mdr2-KOFoxl1-CRE;RosaYFP mouse model, liver progenitor cells are the source of cHCC-CCA tumors, but not the source of HCC. Ablating the progenitors, caused reduction of cHCC-CCA tumors but did not affect HCCs. RNA-sequencing revealed enrichment of the IL-6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. Single-cell RNA-sequencing (scRNA-seq) analysis revealed that IL-6 is expressed by immune and parenchymal cells during senescence, and that IL-6 is part of the senescence-associated secretory phenotype. Administration of an anti-IL-6 antibody to Mdr2-KOFoxl1-CRE;RosaYFP mice inhibited the development of cHCC-CCA tumors. Blocking IL-6 trans-signaling led to a decrease in the number and size of cHCC-CCA tumors, indicating their dependence on this pathway. Furthermore, the administration of a senolytic agent inhibited IL-6 and the development of cHCC-CCA tumors. Conclusion: Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL-6, which derives in part from cells in senescence, plays an important role in this process via IL-6 trans-signaling. These findings could be applied to develop new therapeutic approaches for cHCC-CCA tumors. Lay summary: Combined hepatocellular carcinoma–cholangiocarcinoma is the third most prevalent type of primary liver cancer (i.e. a cancer that originates in the liver). Herein, we show that this type of cancer originates in stem cells in the liver and that it depends on inflammatory signaling. Specifically, we identify a cytokine called IL-6 that appears to be important in the development of these tumors. Our results could be used for the development of novel treatments for these aggressive tumors.

Original languageAmerican English
Pages (from-to)1631-1641
Number of pages11
JournalJournal of Hepatology
Issue number6
StatePublished - Dec 2022

Bibliographical note

Publisher Copyright:
© 2022 European Association for the Study of the Liver


  • Cancer stem cells
  • Hepatocarcinogenesis
  • Inflammation-induced cancer
  • Oval cells


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