Department of Cell Biology and Department of Cardiovascular Surgery, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 57 Zhugan Lane, Hangzhou 310000, Zhejiang, China; Department of Pathology, Zhejiang Hospital, Zhejiang University School of Medicine, 12 Lingyin Rd, Hangzhou 310013, Zhejiang, China.
Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, 38 Xihu Rd, Hangzhou 310009, Zhejiang, China.
Int J Biol Macromol. 2024 May;268(Pt 1):131560. doi: 10.1016/j.ijbiomac.2024.131560. Epub 2024 Apr 15.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis. Cancer-associated fibroblasts (CAFs) play a critical role in regulating TNBC tumor development. This study aimed to identify and characterize a specific subtype of CAFs associated with TNBC. Initially, using high-throughput bulk transcriptomic data in two cohorts, we identified three CAF-related subtypes (CS1, CS2, CS3) in TNBC samples. These three CAFs subtypes were closely linked to the tumor microenvironment. The CS1 subtype exhibited a relatively immune-rich microenvironment and a favourable prognosis, whereas the CS3 subtype displayed an immune-deprived tumor microenvironment and an unfavourable prognosis. Through WGCNA analysis, POSTN was identified as a key biomarker for CAFs associated with TNBC. Then, POSTNCAFs was identified and characterized. Both POSTN and POSTNCAFs showed significant positive correlations with stromal molecules HGF and MET at both the transcriptional and protein levels. Specifically co-localized with CAFs in the tumor stromal area, POSTN, produced by POSTNCAFs, could modulate the HGF-MET axis, serving as a bypass activation pathway to regulate tumor cell proliferation in response to EGFR inhibitor and MET inhibitor. This study underscores the significance of POSTN and POSTNCAFs as crucial targets for the diagnosis and treatment of TNBC.
三阴性乳腺癌（TNBC）是一种预后较差的乳腺癌亚型。癌症相关成纤维细胞（CAFs）在调节 TNBC 肿瘤发展中起着关键作用。本研究旨在鉴定和表征与 TNBC 相关的特定 CAF 亚型。最初，我们使用两个队列中的高通量批量转录组数据，在 TNBC 样本中鉴定出三种与 CAF 相关的亚型（CS1、CS2、CS3）。这三种 CAFs 亚型与肿瘤微环境密切相关。CS1 亚型表现出相对丰富的免疫微环境和良好的预后，而 CS3 亚型则表现出免疫剥夺的肿瘤微环境和不良的预后。通过 WGCNA 分析，POSTN 被鉴定为与 TNBC 相关的 CAFs 的关键生物标志物。然后，鉴定并表征了 POSTNCAFs。POSTN 和 POSTNCAFs 在转录和蛋白水平上均与基质分子 HGF 和 MET 呈显著正相关。POSTN 特异性地在肿瘤基质区域与 CAFs 共定位，由 POSTNCAFs 产生的 POSTN 可以调节 HGF-MET 轴，作为旁路激活途径，以响应 EGFR 抑制剂和 MET 抑制剂调节肿瘤细胞增殖。这项研究强调了 POSTN 和 POSTNCAFs 作为 TNBC 诊断和治疗的关键靶标的重要性。
Int J Biol Macromol. 2024-5
Front Mol Biosci. 2025-3-31
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