Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations.
Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations.
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DOI：
10.1016/j.ccell.2021.03.012
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发表时间：
2021-06-14
期刊：
影响因子：
50.3
通讯作者：
Schwabe RF
中科院分区：
文献类型：
--
作者：
Affo S;Nair A;Brundu F;Ravichandra A;Bhattacharjee S;Matsuda M;Chin L;Filliol A;Wen W;Song X;Decker A;Worley J;Caviglia JM;Yu L;Yin D;Saito Y;Savage T;Wells RG;Mack M;Zender L;Arpaia N;Remotti HE;Rabadan R;Sims P;Leblond AL;Weber A;Riener MO;Stockwell BR;Gaublomme J;Llovet JM;Kalluri R;Michalopoulos GK;Seki E;Sia D;Chen X;Califano A;Schwabe RF
癌症相关成纤维细胞（CAF）在肝癌中是一个特征不明显的细胞群。我们的研究探讨了CAF在肝内胆管癌（ICC）中的功能，这是一种高度结缔组织增生的肝脏肿瘤。遗传追踪、单细胞rna测序和配体受体分析发现，肝星状细胞（HSC）是CAF的主要来源，而HSC衍生的CAF是与肿瘤细胞相互作用的优势群体。在小鼠中，CAF促进ICC进展，正如hsc选择性CAF耗尽所揭示的那样。在患者中，高的panCAF特征与生存率降低和复发率增加有关。单细胞rna测序将CAF分离为炎症和生长因子富集亚群（iCAF）和肌成纤维细胞亚群（myCAF），显示出不同的配体-受体相互作用。mycafa表达透明质酸合成酶2，但不表达I型胶原，促进ICC。表达CAF的HGF通过肿瘤表达MET促进ICC生长，从而直接将CAF与肿瘤细胞联系起来。总之，我们的数据表明，可靶向治疗的CAF亚型特异性介质可促进结缔组织增生ICC的生长，而I型胶原则不能。肝内胆管癌（ICC）是一种异常僵硬的肝脏肿瘤，由于大量形成疤痕的癌相关成纤维细胞（CAF）。在这里，Affo等人确定了CAF的起源和功能，并揭示了不同的CAF亚群，通过不同的治疗靶向介质促进ICC生长。因此，CAF及其介质可作为ICC的治疗靶点。
Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly desmoplastic liver tumor. Genetic tracing, single-cell RNA-sequencing and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF, and HSC-derived CAF as dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA-sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2 but not type I collagen, promotes ICC. iCAF-expressed HGF enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen. Intrahepatic cholangiocarcinoma (ICC) is an extraordinarily stiff liver tumor due to abundant scar-forming cancer-associated fibroblasts (CAF). Here, Affo et al. determine origin and functions of CAF, and uncover distinct CAF subsets, promoting ICC growth via different therapeutically targetable mediators. Thus, CAF and their mediators may serve as therapeutic targets for ICC.
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影响因子：
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Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
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