Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer
Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer
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DOI：
10.1007/s00109-023-02384-7
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发表时间：
2023-10
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通讯作者：
F. Takatsu;K. Suzawa;S. Tomida;Yin Min Thu;M. Sakaguchi;T. Toji;Masayoshi Ohki;S. Tsudaka;Keiichi Date;Naoki Matsuda;Kazuma Iwata;Yidan Zhu;K. Nakata;K. Shien;H. Yamamoto;Akiko Nakayama;M. Okazaki;S. Sugimoto;Shinichi Toyooka
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作者：
F. Takatsu;K. Suzawa;S. Tomida;Yin Min Thu;M. Sakaguchi;T. Toji;Masayoshi Ohki;S. Tsudaka;Keiichi Date;Naoki Matsuda;Kazuma Iwata;Yidan Zhu;K. Nakata;K. Shien;H. Yamamoto;Akiko Nakayama;M. Okazaki;S. Sugimoto;Shinichi Toyooka
癌症相关成纤维细胞（CAF）是肿瘤微环境中的重要组成部分，我们试图在CAF中确定非小细胞肺癌（NSCLC）的有效治疗靶点。在这项研究中，我们建立了成纤维细胞系的癌和非癌部分的手术肺标本与NSCLC患者，并评估对NSCLC细胞的行为的差异。进行RNA测序分析以研究正常成纤维细胞（NF）和CAFs之间的差异表达基因，并且我们确定了已知在各种实体瘤中过表达并促进癌症进展的骨膜蛋白（POSTIN）在CAFs中的表达显著高于NF。PO 4通过激活NSCLC细胞的ERK途径增加细胞增殖，并诱导上皮-间质转化（EMT），从而改善体外迁移。此外，在CAF中敲低POST 3抑制了这些作用，并且体内实验证明，POST 3敲低提高了EGFR突变型NSCLC细胞对奥希替尼治疗的敏感性。总的来说，我们的研究结果表明，CAF衍生的POR 4参与了NSCLC的肿瘤生长，迁移，EMT诱导和耐药性。靶向CAF分泌的POR 4可能是NSCLC的潜在治疗策略。关键信息·与NCSLC中的正常成纤维细胞相比，POR 4在CAF中显著上调。·通过激活NSCLC细胞的ERK通路，POL 4可增加细胞增殖。POT 3诱导NSCLC细胞中的EMT并提高迁移能力。P013基因敲减提高了EGFR突变型NSCLC细胞对奥希替尼的敏感性。
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.