Cellular heterogeneity and transcriptomic profiles during intrahepatic cholangiocarcinoma initiation and progression
Hepatology, vol. 76, pp. 1302–1317
Abstract
BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is not fully investigated, and how stromal cells contribute to ICC formation is poorly understood. We aimed to uncover ICC origin, cellular heterogeneity, and critical modulators during ICC initiation/progression, and to decipher how fibroblast and endothelial cells in the stromal compartment favor ICC progression. APPROACH AND RESULTS: We performed single-cell RNA sequencing (scRNA-seq) using AKT/Notch intracellular domain-induced mouse ICC tissues at early, middle, and late stages. We analyzed the transcriptomic landscape, cellular classification and evolution, and intercellular communication during ICC initiation/progression. We confirmed the findings using quantitative real-time PCR, western blotting, immunohistochemistry or immunofluorescence, and gene knockout/knockdown analysis. We identified stress-responding and proliferating subpopulations in late-stage mouse ICC tissues and validated them using human scRNA-seq data sets. By integrating weighted correlation network analysis and protein-protein interaction through least absolute shrinkage and selection operator regression, we identified zinc finger, MIZ-type containing 1 (Zmiz1) and Y box protein 1 (Ybx1) as core transcription factors required by stress-responding and proliferating ICC cells, respectively. Knockout of either one led to the blockade of ICC initiation/progression. Using two other ICC mouse models (YAP/AKT, KRAS/p19) and human ICC scRNA-seq data sets, we confirmed the orchestrating roles of Zmiz1 and Ybx1 in ICC occurrence and development. In addition, hes family bHLH transcription factor 1, cofilin 1, and inhibitor of DNA binding 1 were identified as driver genes for ICC. Moreover, periportal liver sinusoidal endothelial cells could differentiate into tip endothelial cells to promote ICC development, and this was Dll4-Notch4-Efnb2 signaling-dependent. CONCLUSIONS: Stress-responding and ICC proliferating subtypes were identified, and Zmiz1 and Ybx1 were revealed as core transcription factors in these subtypes. Fibroblast-endothelial cell interaction promotes ICC development.
Authors 13
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Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
School of Automation Science and Engineering,Faculty of Electronic and Information Engineering,Xi’an Jiaotong University,Xi’an,Shaanxi,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
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Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
School of Pharmacy,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
School of Pharmacy,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
School of Pharmacy,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
School of Automation Science and Engineering,Faculty of Electronic and Information Engineering,Xi’an Jiaotong University,Xi’an,Shaanxi,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
School of Pharmacy,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
Genome Institute,the First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,Shaanxi,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
School of Life Science and Technology,Xi’an Jiaotong University,Xi’an,Shaanxi,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
Genome Institute,the First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,Shaanxi,China
MOE Key Lab for Intelligent Networks & Networks Security,Faculty of Electronic and Information Engineering,Xi’an Jiaotong University,Xi’an,Shaanxi,China
School of Computer Science and Technology,Faculty of Electronic and Information Engineering,Xi’an Jiaotong University,Xi’an,Shaanxi,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
Department of Endocrinology,the First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,Shaanxi,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
School of Life Science and Technology,Xi’an Jiaotong University,Xi’an,Shaanxi,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
-
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
School of Pharmacy,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
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Kai Ye corresponding Aachen Faculty of Science, Leiden University Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Leiden University · Creative Commons · First Affiliated Hospital of Xi'an Jiaotong University · Huazhong University of Science and Technology · Xi'an Jiaotong University
Affiliation as printed
Faculty of Science,Leiden University,Leiden,the Netherlands
Genome Institute,the First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,Shaanxi,China
MOE Key Lab for Intelligent Networks & Networks Security,Faculty of Electronic and Information Engineering,Xi’an Jiaotong University,Xi’an,Shaanxi,China
School of Automation Science and Engineering,Faculty of Electronic and Information Engineering,Xi’an Jiaotong University,Xi’an,Shaanxi,China
School of Life Science and Technology,Xi’an Jiaotong University,Xi’an,Shaanxi,China
Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
Faculty of ScienceLeiden UniversityLeidenthe Netherlands
Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes
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