Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan.
J Mol Med (Berl). 2023 Dec;101(12):1603-1614. doi: 10.1007/s00109-023-02384-7. Epub 2023 Oct 13.
Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells' ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC. KEY MESSAGES: • POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC. • POSTN increases cell proliferation via activation of the NSCLC cells' ERK pathway. • POSTN induces EMT in NSCLC cells and improves the migration ability. • POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.
癌症相关成纤维细胞（CAFs）是肿瘤微环境中的重要组成部分，我们试图确定 CAFs 中非小细胞肺癌（NSCLC）的有效治疗靶点。在这项研究中，我们从 NSCLC 手术肺标本的癌性和非癌性部分建立了成纤维细胞系，并评估了它们对 NSCLC 细胞行为的差异。进行 RNA 测序分析以研究正常成纤维细胞（NFs）和 CAFs 之间差异表达的基因，我们发现骨桥蛋白（POSTN）的表达明显高于 NFs，POSTN 在各种实体瘤中过表达并促进癌症进展。POSTN 通过 NSCLC 细胞的 ERK 途径激活增加细胞增殖，并诱导上皮-间充质转化（EMT），从而改善体外迁移。此外，CAFs 中的 POSTN 敲低抑制了这些效应，体内实验表明 POSTN 敲低提高了 EGFR 突变型 NSCLC 细胞对奥希替尼治疗的敏感性。综上所述，我们的结果表明，CAF 衍生的 POSTN 参与 NSCLC 中的肿瘤生长、迁移、EMT 诱导和耐药性。靶向 CAF 分泌的 POSTN 可能是 NSCLC 的一种潜在治疗策略。关键信息：• POSTN 在 NSCLC 的 CAFs 中明显上调，与正常成纤维细胞相比。• POSTN 通过激活 NSCLC 细胞的 ERK 途径增加细胞增殖。• POSTN 诱导 NSCLC 细胞 EMT 并提高迁移能力。• POSTN 敲低可提高 EGFR 突变型 NSCLC 细胞对奥希替尼的敏感性。
