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

Roberta Melchionna, Sheila Spada, Francesca Di Modugno, Daniel D'Andrea, Anna Di Carlo, Mariangela Panetta, Anna Maria Mileo, Isabella Sperduti, Barbara Antoniani, Enzo Gallo, Rita T Lawlor, Lorenzo Piemonti, Paolo Visca, Michele Milella, Gian Luca Grazi, Francesco Facciolo, Emily Chen, Aldo Scarpa, Paola Nisticò

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)e50078
JournalEMBO Reports
Volume21
Issue number11
DOIs
Publication statusPublished - Nov 5 2020

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