Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 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 Amran; Sofie 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

doi:10.1016/j.jhep.2022.07.029

Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 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 journal › Article › Academic › peer-review

Abstract

BACKGROUND AND 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.

METHOD: To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor an 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, as we have first observed.

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-seq revealed enrichment of the IL6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. ScRNA-seq analysis revealed that IL6 is expressed from immune and parenchymal cells in senescence, and that IL6 is part of the senescence-associated secretory phenotype (SASP). Administration of anti-IL6 Ab to Mdr2-KOFoxl1-CRE;RosaYFP mice, inhibited the development of cHCC-CCA tumors. By blocking IL6 trans-signaling, cHCC-CCA tumors decreased in number and size, indicating that cHCC-CCA is dependent on IL6 trans-signaling. Furthermore, the administration of a senolytic agent inhibited IL6 and the development of cHCC-CCA tumors.

CONCLUSION: Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL6, which derives in part from cells in senescence, plays an important role in this process via IL6 trans-signaling. These findings could enhance new therapeutic approaches for cHCC-CCA liver cancer.

LAY SUMMARY: Combined hepatocellular carcinoma - cholangiocarcinoma is the third prevalent liver cancer. We show that the source of this tumor is the liver tissue stem cells and that, this tumor type is dependent on an inflammatory signaling of IL6 and can be inhibited by blocking IL6 signaling or using a senolytic agent.

Original language	English
Pages (from-to)	1631-1641
Number of pages	12
Journal	Journal of Hepatology
Volume	77
Issue number	6
Early online date	18 Aug 2022
DOIs	https://doi.org/10.1016/j.jhep.2022.07.029
Publication status	Published - Dec 2022

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10.1016/j.jhep.2022.07.029Licence: Free access - publisher

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Rosenberg, N., Van Haele, M., Lanton, T., Brashi, N., Bromberg, Z., Adler, H., Giladi, H., Peled, A., Goldenberg, D. S., Axelrod, J. H., Simerzin, A., Chai, C., Paldor, M., Markezana, A., Yaish, D., Shemulian, Z., Gross, D., Barnoy, S., Gefen, M., ... Galun, E. (2022). Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling. Journal of Hepatology, 77(6), 1631-1641. https://doi.org/10.1016/j.jhep.2022.07.029

@article{d57c548d542949348f7c86ffde92aab1,

title = "Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling",

abstract = "BACKGROUND AND 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.METHOD: To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor an 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, as we have first observed.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-seq revealed enrichment of the IL6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. ScRNA-seq analysis revealed that IL6 is expressed from immune and parenchymal cells in senescence, and that IL6 is part of the senescence-associated secretory phenotype (SASP). Administration of anti-IL6 Ab to Mdr2-KOFoxl1-CRE;RosaYFP mice, inhibited the development of cHCC-CCA tumors. By blocking IL6 trans-signaling, cHCC-CCA tumors decreased in number and size, indicating that cHCC-CCA is dependent on IL6 trans-signaling. Furthermore, the administration of a senolytic agent inhibited IL6 and the development of cHCC-CCA tumors.CONCLUSION: Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL6, which derives in part from cells in senescence, plays an important role in this process via IL6 trans-signaling. These findings could enhance new therapeutic approaches for cHCC-CCA liver cancer.LAY SUMMARY: Combined hepatocellular carcinoma - cholangiocarcinoma is the third prevalent liver cancer. We show that the source of this tumor is the liver tissue stem cells and that, this tumor type is dependent on an inflammatory signaling of IL6 and can be inhibited by blocking IL6 signaling or using a senolytic agent.",

author = "Nofar Rosenberg and {Van Haele}, Matthias and Tali Lanton and Neta Brashi and Zohar Bromberg and Hanan Adler and Hilla Giladi and Amnon Peled and Goldenberg, {Daniel S} and Axelrod, {Jonathan H} and Alina Simerzin and Chofit Chai and Mor Paldor and Auerlia Markezana and Dayana Yaish and Zohar Shemulian and Dvora Gross and Shanny Barnoy and Maytal Gefen and Osher Amran and Sofie Claerhout and Mirian Fern{\'a}ndez-Vaquero and Mar{\'i}a Garc{\'i}a-Beccaria and Danijela Heide and Michal Shoshkes-Carmel and {Schmidt Arras}, Dirk and Sharona Elgavish and Yuval Nevo and Hadar Benyamini and Tirnitz-Parker, {Janina E E} and Aranzazu Sanchez and Blanca Herrera and Rifaat Safadi and Kaestner, {Klaus H} and Stefan Rose-John and Tania Roskams and Mathias Heikenwalder and Eithan Galun",

year = "2022",

month = dec,

doi = "10.1016/j.jhep.2022.07.029",

language = "English",

volume = "77",

pages = "1631--1641",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier Science",

number = "6",

}

Rosenberg, N, Van Haele, M, Lanton, T, Brashi, N, Bromberg, Z, Adler, H, Giladi, H, Peled, A, Goldenberg, DS, Axelrod, JH, Simerzin, A, Chai, C, Paldor, M, Markezana, A, Yaish, D, Shemulian, Z, Gross, D, Barnoy, S, Gefen, M, Amran, O, Claerhout, S, Fernández-Vaquero, M, García-Beccaria, M, Heide, D, Shoshkes-Carmel, M, Schmidt Arras, D, Elgavish, S, Nevo, Y, Benyamini, H, Tirnitz-Parker, JEE, Sanchez, A, Herrera, B, Safadi, R, Kaestner, KH, Rose-John, S, Roskams, T, Heikenwalder, M & Galun, E 2022, 'Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling', Journal of Hepatology, vol. 77, no. 6, pp. 1631-1641. https://doi.org/10.1016/j.jhep.2022.07.029

TY - JOUR

T1 - Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling

AU - Rosenberg, Nofar

AU - Van Haele, Matthias

AU - Lanton, Tali

AU - Brashi, Neta

AU - Bromberg, Zohar

AU - Adler, Hanan

AU - Giladi, Hilla

AU - Peled, Amnon

AU - Goldenberg, Daniel S

AU - Axelrod, Jonathan H

AU - Simerzin, Alina

AU - Chai, Chofit

AU - Paldor, Mor

AU - Markezana, Auerlia

AU - Yaish, Dayana

AU - Shemulian, Zohar

AU - Gross, Dvora

AU - Barnoy, Shanny

AU - Gefen, Maytal

AU - Amran, Osher

AU - Claerhout, Sofie

AU - Fernández-Vaquero, Mirian

AU - García-Beccaria, María

AU - Heide, Danijela

AU - Shoshkes-Carmel, Michal

AU - Schmidt Arras, Dirk

AU - Elgavish, Sharona

AU - Nevo, Yuval

AU - Benyamini, Hadar

AU - Tirnitz-Parker, Janina E E

AU - Sanchez, Aranzazu

AU - Herrera, Blanca

AU - Safadi, Rifaat

AU - Kaestner, Klaus H

AU - Rose-John, Stefan

AU - Roskams, Tania

AU - Heikenwalder, Mathias

AU - Galun, Eithan

PY - 2022/12

Y1 - 2022/12

N2 - BACKGROUND AND 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.METHOD: To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor an 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, as we have first observed.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-seq revealed enrichment of the IL6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. ScRNA-seq analysis revealed that IL6 is expressed from immune and parenchymal cells in senescence, and that IL6 is part of the senescence-associated secretory phenotype (SASP). Administration of anti-IL6 Ab to Mdr2-KOFoxl1-CRE;RosaYFP mice, inhibited the development of cHCC-CCA tumors. By blocking IL6 trans-signaling, cHCC-CCA tumors decreased in number and size, indicating that cHCC-CCA is dependent on IL6 trans-signaling. Furthermore, the administration of a senolytic agent inhibited IL6 and the development of cHCC-CCA tumors.CONCLUSION: Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL6, which derives in part from cells in senescence, plays an important role in this process via IL6 trans-signaling. These findings could enhance new therapeutic approaches for cHCC-CCA liver cancer.LAY SUMMARY: Combined hepatocellular carcinoma - cholangiocarcinoma is the third prevalent liver cancer. We show that the source of this tumor is the liver tissue stem cells and that, this tumor type is dependent on an inflammatory signaling of IL6 and can be inhibited by blocking IL6 signaling or using a senolytic agent.

AB - BACKGROUND AND 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.METHOD: To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor an 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, as we have first observed.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-seq revealed enrichment of the IL6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. ScRNA-seq analysis revealed that IL6 is expressed from immune and parenchymal cells in senescence, and that IL6 is part of the senescence-associated secretory phenotype (SASP). Administration of anti-IL6 Ab to Mdr2-KOFoxl1-CRE;RosaYFP mice, inhibited the development of cHCC-CCA tumors. By blocking IL6 trans-signaling, cHCC-CCA tumors decreased in number and size, indicating that cHCC-CCA is dependent on IL6 trans-signaling. Furthermore, the administration of a senolytic agent inhibited IL6 and the development of cHCC-CCA tumors.CONCLUSION: Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL6, which derives in part from cells in senescence, plays an important role in this process via IL6 trans-signaling. These findings could enhance new therapeutic approaches for cHCC-CCA liver cancer.LAY SUMMARY: Combined hepatocellular carcinoma - cholangiocarcinoma is the third prevalent liver cancer. We show that the source of this tumor is the liver tissue stem cells and that, this tumor type is dependent on an inflammatory signaling of IL6 and can be inhibited by blocking IL6 signaling or using a senolytic agent.

U2 - 10.1016/j.jhep.2022.07.029

DO - 10.1016/j.jhep.2022.07.029

M3 - Article

C2 - 35988690

SN - 0168-8278

VL - 77

SP - 1631

EP - 1641

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 6

ER -