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 language | English |
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Journal | EMBO Rep. |
Volume | 21 |
Issue number | 11 |
DOIs | |
Publication status | Published - 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