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

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Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling
Journal of Hepatology ( IF 25.7 ) Pub Date : 2022-08-18 , DOI: 10.1016/j.jhep.2022.07.029
Nofar Rosenberg ₁ , Matthias Van Haele ₂ , Tali Lanton ₁ , Neta Brashi ₁ , Zohar Bromberg ₁ , Hanan Adler ₁ , Hilla Giladi ₁ , Amnon Peled ₁ , Daniel S Goldenberg ₁ , Jonathan H Axelrod ₁ , Alina Simerzin ₁ , Chofit Chai ₁ , Mor Paldor ₁ , Auerlia Markezana ₁ , Dayana Yaish ₁ , Zohar Shemulian ₁ , Dvora Gross ₁ , Shanny Barnoy ₁ , Maytal Gefen ₁ , Osher Amran ₁ , Sofie Claerhout ₃ , Mirian Fernández-Vaquero ₄ , María García-Beccaria ₄ , Danijela Heide ₄ , Michal Shoshkes-Carmel ₅ , Dirk Schmidt Arras ₆ , Sharona Elgavish ₇ , Yuval Nevo ₇ , Hadar Benyamini ₇ , Janina E E Tirnitz-Parker ₈ , Aranzazu Sanchez ₉ , Blanca Herrera ₉ , Rifaat Safadi ₁₀ , Klaus H Kaestner ₅ , Stefan Rose-John ₁₁ , Tania Roskams ₃ , Mathias Heikenwalder ₁₂ , Eithan Galun ₁

Affiliation

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium; Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Center for Translational Research, Philadelphia, USA.
Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany; Department of Biosciences, University of Salzburg, Salzburg, Austria.
Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Centre for Medical Research, University of Western Australia & Harry Perkins Institute of Medical Research, Crawley, Australia.
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Spain.
The Liver Institute, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; The M3 Research Institute, Rosenauer Weg 30, Medical Faculty Tuebingen (MFT), 72076 Tuebingen, Germany.

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-KO^{Foxl1-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-KO^{Foxl1-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-KO^{Foxl1-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.

中文翻译：

合并肝细胞-胆管癌来源于肝祖细胞并依赖于衰老和 IL-6 转导信号

背景与目标

原发性肝癌包括肝细胞癌 (HCC)、肝内胆管癌 (CCA) 和 HCC-CCA 联合肿瘤 (cHCC-CCA)。有人提出，但尚未明确证明，肝祖细胞(HPC) 可促进肝癌发生。我们的目的是确定 HPC 是否会导致 HCC、cHCC-CCA 或这两种类型的肿瘤。

方法

为了在肝癌发生过程中追踪祖细胞，我们生成了 Mdr2 -KO 小鼠，这些小鼠带有黄色荧光蛋白 (YFP) 报告基因，该基因由Foxl1启动子驱动，该启动子在祖细胞中特异性表达。这些小鼠 ( Mdr2 -KO ^{Foxl1-CRE；RosaYFP}) 在 14-16 个月大时出现慢性炎症和 HCC，随后在 18 个月大时出现 cHCC-CCA 肿瘤。

结果

在这个Mdr2 -KO ^{Foxl1-CRE;RosaYFP}小鼠模型中，肝祖细胞是 cHCC-CCA 肿瘤的来源，但不是 HCC 的来源。消融祖细胞导致 cHCC-CCA 肿瘤减少，但不影响 HCC。RNA 测序揭示了与 HCC 肿瘤相比，cHCC-CCA 肿瘤中 IL-6 信号通路的富集。单细胞 RNA 测序 (scRNA-seq) 分析表明，IL-6 在衰老过程中由免疫细胞和实质细胞表达，并且 IL-6 是衰老相关分泌表型的一部分。将抗 IL-6 抗体用于Mdr2 -KO ^{Foxl1-CRE；RosaYFP}小鼠抑制 cHCC-CCA 肿瘤的发展。阻断 IL-6 转导信号导致 cHCC-CCA 肿瘤的数量和大小减少，表明它们依赖于该通路。此外，使用衰老清除剂可抑制 IL-6 和 cHCC-CCA 肿瘤的发展。