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

R. Melchionna, S. Spada, F. Di Modugno, D. D'Andrea, A. Di Carlo, M. Panetta, A.M. Mileo, I. Sperduti, B. Antoniani, E. Gallo, R.T. Lawlor, L. Piemonti, P. Visca, M. Milella, G.L. Grazi, F. Facciolo, E. Chen, A. Scarpa, P. 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. © 2020 The Authors. Published under the terms of the CC BY 4.0 license
Original languageEnglish
JournalEMBO Rep.
Volume21
Issue number11
DOIs
Publication statusPublished - 2020

Keywords

  • actin cytoskeleton
  • AXL
  • cancer-associated fibroblasts
  • GAS6
  • lung cancer
  • AXL protein
  • growth arrest specific protein 6
  • hMENA protein
  • regulator protein
  • unclassified drug
  • Article
  • cancer associated fibroblast
  • cancer prognosis
  • cancer resistance
  • cell interaction
  • controlled study
  • epithelial mesenchymal transition
  • gene overexpression
  • human
  • human cell
  • immune evasion
  • intracellular signaling
  • liquid chromatography-mass spectrometry
  • lung non-small cell carcinoma cell line
  • non small cell lung cancer
  • pancreas adenocarcinoma
  • pancreatic adenocarcinoma cell line
  • priority journal
  • protein function
  • protein secretion
  • proteomics
  • regulatory mechanism
  • tumor invasion
  • tumor promotion

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