CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China.
Molecular Pathology Laboratory, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Shanghai, 201800, People's Republic of China.
Genome Med. 2024 Aug 13;16(1):98. doi: 10.1186/s13073-024-01367-8.
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.
背景：癌症相关成纤维细胞（CAFs）是肿瘤微环境（TME）中的主要细胞类型，并且已经在各种肿瘤中鉴定出 CAF 亚群。然而，CAFs 如何在肝 TME 中与其他细胞群体空间协调以促进癌症进展仍不清楚。
方法：我们结合多区域蛋白质组学（6 名患者，24 个样本）、10X Genomics Visium 空间转录组学（11 名患者，25 个样本）和多重成像（92 名患者，264 个样本）技术，以解析成纤维细胞的表达异质性、功能多样性、空间分布、共定位和相互作用。通过从 5 名肝癌患者分离的细胞和体外功能测定验证了新鉴定的 CAF 亚群。
结果：我们鉴定出一种肝 CAF 亚群，其特征在于 COL1A2、COL4A1、COL4A2、CTGF 和 FSTL1 的表达，并将其命名为 F5-CAF。F5-CAF 优先位于肿瘤巢内和周围，并与肝癌中的具有更高干性的癌细胞共定位。92 名患者的多重染色和 371 名患者的批量转录组学表明，F5-CAF 在 HCC 中的丰度与预后不良相关。进一步的体外实验表明，从肝癌患者中分离的 F5-CAF 可以促进 HCC 细胞的增殖和干性。
结论：我们在肝癌中鉴定出一种 CAF 亚群 F5-CAF，它与癌症干性和不良预后相关。我们的结果提供了潜在的机制，即 TME 中的 CAF 亚群通过支持癌症干细胞的存活来促进肝癌的发展。
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