2. Academic Validation
  3. 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.
PMID: 32909687 DOI: 10.15252/embr.202050078
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.

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