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Abstract：
BACKGROUND: Cancer-associated fibroblasts (CAFs) are the prominent cell type in the tumor microenvironment (TME), and CAF subsets have been identified in various tumors. However, how CAFs spatially coordinate other cell populations within the liver TME to promote cancer progression remains unclear.
METHODS: We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays.
RESULTS: We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells.
CONCLUSIONS: We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells.
METHODS: We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays.
RESULTS: We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells.
CONCLUSIONS: We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells.
摘要：
背景：癌症相关成纤维细胞（CAF）是肿瘤微环境（TME）中突出的细胞类型，已经在各种肿瘤中鉴定了CAF亚群。然而,CAF如何在空间上协调肝脏TME内的其他细胞群体以促进癌症进展尚不清楚.
方法：我们结合了多区域蛋白质组学（6例患者，24个样本)，10X基因组学空间转录组学(11名患者，25个样品)，和多重成像(92名患者，264个样本)破译表达异质性的技术，功能多样性，空间分布，共同定位，和成纤维细胞的相互作用。通过从5名肝癌患者中分离的细胞和体外功能测定来验证新鉴定的CAF亚群。
结果：我们确定了肝脏CAF亚群，以COL1A2、COL4A1、COL4A2、CTGF、和FSTL1，并命名为F5-CAF。F5-CAF优先位于肿瘤巢内和周围，并与肝细胞癌（HCC）中具有较高干性的癌细胞共定位。92例患者的多重染色和371例患者的大量转录组表明，HCC中F5-CAFs的丰度与预后较差有关。进一步的体外实验表明，从肝癌患者中分离的F5-CAFs可以促进HCC细胞的增殖和干性。
结论：我们确定了肝癌中的CAF亚群F5-CAF，这与癌症的干性和不良预后有关。我们的结果提供了TME中CAF亚群通过支持癌症干细胞的存活来促进肝癌发展的潜在机制。
方法：我们结合了多区域蛋白质组学（6例患者，24个样本)，10X基因组学空间转录组学(11名患者，25个样品)，和多重成像(92名患者，264个样本)破译表达异质性的技术，功能多样性，空间分布，共同定位，和成纤维细胞的相互作用。通过从5名肝癌患者中分离的细胞和体外功能测定来验证新鉴定的CAF亚群。
结果：我们确定了肝脏CAF亚群，以COL1A2、COL4A1、COL4A2、CTGF、和FSTL1，并命名为F5-CAF。F5-CAF优先位于肿瘤巢内和周围，并与肝细胞癌（HCC）中具有较高干性的癌细胞共定位。92例患者的多重染色和371例患者的大量转录组表明，HCC中F5-CAFs的丰度与预后较差有关。进一步的体外实验表明，从肝癌患者中分离的F5-CAFs可以促进HCC细胞的增殖和干性。
结论：我们确定了肝癌中的CAF亚群F5-CAF，这与癌症的干性和不良预后有关。我们的结果提供了TME中CAF亚群通过支持癌症干细胞的存活来促进肝癌发展的潜在机制。
