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
  • 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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