The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation

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/hMENA?v6 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 revealed that CAF over-expressing hMENA?v6 secret the AXL ligand GAS6, favoring the invasiveness of AXL-expressing PDAC and NSCLC cells. Reciprocally, hMENA/hMENA?v6 regulate 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 pancreatic (PDAC) and lung cancer (NSCLC) patients. We argue that hMENA contributes to cancer progression through paracrine tumor-stroma crosstalk, with far-reaching novel prognostic and therapeutic implications for tailored therapies in NSCLC and PDAC.