The dynamic interplay between cancer cells and cancer‐associated fibroblasts (CAFs) is regulated by multiple signaling pathways, which can lead to cancer progression and therapy resistance. We have previously demonstrated that hMENA, a member of the actin regulatory protein of Ena/VASP family, and its tissue‐specific isoforms influence a number of intracellular signaling pathways related to cancer progression. Here, we report a novel function of hMENA/hMENAΔv6 isoforms in tumor‐promoting CAFs and in the modulation of pro‐tumoral cancer cell/CAF crosstalk via GAS6/AXL axis regulation. LC‐MS/MS proteomic analysis reveals that CAFs that overexpress hMENAΔv6 secrete the AXL ligand GAS6, favoring the invasiveness of AXL‐expressing pancreatic ductal adenocarcinoma (PDAC) and non‐small cell lung cancer (NSCLC) cells. Reciprocally, hMENA/hMENAΔv6 regulates AXL expression in tumor cells, thus sustaining GAS6‐AXL axis, reported as crucial in EMT, immune evasion, and drug resistance. Clinically, we found that a high hMENA/GAS6/AXL gene expression signature is associated with a poor prognosis in PDAC and NSCLC. We propose that hMENA contributes to cancer progression through paracrine tumor–stroma crosstalk, with far‐reaching prognostic and therapeutic implications for NSCLC and PDAC.

中文翻译：

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肌动蛋白调节剂 hMENA 调节 GAS6-AXL 轴和促肿瘤癌症/基质细胞的合作。

癌细胞和癌症相关成纤维细胞 (CAF) 之间的动态相互作用受到多种信号通路的调节，这可能导致癌症进展和治疗抵抗。我们之前已经证明 hMENA 是 Ena/VASP 家族肌动蛋白调节蛋白的成员，其组织特异性同种型影响许多与癌症进展相关的细胞内信号通路。在这里，我们报告了 hMENA/hMENAΔv6 同工型在促进肿瘤的 CAF 和通过 GAS6/AXL 轴调节调节促肿瘤癌细胞/CAF 串扰中的新功能。LC-MS/MS 蛋白质组学分析表明，过表达 hMENAΔv6 的 CAF 分泌 AXL 配体 GAS6，有利于表达 AXL 的胰腺导管腺癌 (PDAC) 和非小细胞肺癌 (NSCLC) 细胞的侵袭性。反过来说，hMENA/hMENAΔv6 调节肿瘤细胞中的 AXL 表达，从而维持 GAS6-AXL 轴，据报道在 EMT、免疫逃避和耐药性中至关重要。临床上，我们发现高 hMENA/GAS6/AXL 基因表达特征与 PDAC 和 NSCLC 的不良预后相关。我们提出，hMENA 通过旁分泌肿瘤-间质串扰促进癌症进展，对 NSCLC 和 PDAC 具有深远的预后和治疗意义。