1. Academic Validation
  2. The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation

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

  • EMBO Rep. 2020 Nov 5;21(11):e50078. doi: 10.15252/embr.202050078.
Roberta Melchionna 1 Sheila Spada 1 Francesca Di Modugno 1 Daniel D'Andrea 2 Anna Di Carlo 1 Mariangela Panetta 1 Anna Maria Mileo 1 Isabella Sperduti 3 Barbara Antoniani 4 Enzo Gallo 4 Rita T Lawlor 5 Lorenzo Piemonti 6 Paolo Visca 4 Michele Milella 7 Gian Luca Grazi 8 Francesco Facciolo 9 Emily Chen 10 Aldo Scarpa 5 Paola Nisticò 1
Affiliations

Affiliations

  • 1 Tumor Immunology and Immunotherapy Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 2 Department of Medicine, Centre for Cell Signaling and Inflammation, Imperial College London, London, UK.
  • 3 Biostatistics and Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 4 Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 5 ARC-NET Research Centre, Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.
  • 6 Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 7 Department of Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 8 Hepato-pancreato-biliary Surgery Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 9 Thoracic-Surgery Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 10 Thermo Fisher Precision Medicine Science Center, Cambridge, MA, USA.
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.

Keywords

AXL; GAS6; actin cytoskeleton; cancer-associated fibroblasts; lung cancer.

Figures
Products