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

doi:10.15252/embr.202050078

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

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article › peer-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 language	English
Journal	EMBO Rep.
Volume	21
Issue number	11
DOIs	https://doi.org/10.15252/embr.202050078
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

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Melchionna, R., Spada, S., Di Modugno, F., D'Andrea, D., Di Carlo, A., Panetta, M., Mileo, A. M., Sperduti, I., Antoniani, B., Gallo, E., Lawlor, R. T., Piemonti, L., Visca, P., Milella, M., Grazi, G. L., Facciolo, F., Chen, E., Scarpa, A., & Nisticò, P. (2020). The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation: EMBO Reports. EMBO Rep., 21(11). https://doi.org/10.15252/embr.202050078

The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation : EMBO Reports. / Melchionna, R.; Spada, S.; Di Modugno, F.; D'Andrea, D.; Di Carlo, A.; Panetta, M.; Mileo, A.M.; Sperduti, I.; Antoniani, B.; Gallo, E.; Lawlor, R.T.; Piemonti, L.; Visca, P.; Milella, M.; Grazi, G.L.; Facciolo, F.; Chen, E.; Scarpa, A.; Nisticò, P.

In: EMBO Rep., Vol. 21, No. 11, 2020.

Research output: Contribution to journal › Article › peer-review

Melchionna, R, Spada, S, Di Modugno, F, D'Andrea, D, Di Carlo, A, Panetta, M, Mileo, AM, Sperduti, I, Antoniani, B, Gallo, E, Lawlor, RT, Piemonti, L, Visca, P, Milella, M, Grazi, GL, Facciolo, F, Chen, E, Scarpa, A & Nisticò, P 2020, 'The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation: EMBO Reports', EMBO Rep., vol. 21, no. 11. https://doi.org/10.15252/embr.202050078

Melchionna, R. ; Spada, S. ; Di Modugno, F. ; D'Andrea, D. ; Di Carlo, A. ; Panetta, M. ; Mileo, A.M. ; Sperduti, I. ; Antoniani, B. ; Gallo, E. ; Lawlor, R.T. ; Piemonti, L. ; Visca, P. ; Milella, M. ; Grazi, G.L. ; Facciolo, F. ; Chen, E. ; Scarpa, A. ; Nisticò, P. / The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation : EMBO Reports. In: EMBO Rep. 2020 ; Vol. 21, No. 11.

@article{3f3447937434493792abd374ac96c85f,

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

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. {\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license",

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",

author = "R. Melchionna and S. Spada and {Di Modugno}, F. and D. D'Andrea and {Di Carlo}, A. and M. Panetta and A.M. Mileo and I. Sperduti and B. Antoniani and E. Gallo and R.T. Lawlor and L. Piemonti and P. Visca and M. Milella and G.L. Grazi and F. Facciolo and E. Chen and A. Scarpa and P. Nistic{\`o}",

note = "Cited By :2 Export Date: 11 March 2021 CODEN: ERMEA Correspondence Address: Nistic{\`o}, P.; Tumor Immunology and Immunotherapy Unit, Italy; email: paola.nistico@ifo.gov.it Funding details: 1,000, 12182, IG 19822 Funding text 1: We thank all patients who donated samples for this study. We thank Giuliana Falasca, Maria Vincenza Sarcone and Vittoria Balzano for technical assistance. This work was supported by the Italian Association for Cancer Research AIRC: 5???1,000, 12182 (P.N., A.S.) and IG 19822 (P.N.). Synopsis image was created with BioRender.com (http://biorender.com/).",

year = "2020",

doi = "10.15252/embr.202050078",

language = "English",

volume = "21",

journal = "EMBO Rep.",

issn = "1469-221X",

publisher = "Wiley-VCH Verlag",

number = "11",

}

TY - JOUR

T1 - The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation

T2 - EMBO Reports

AU - Melchionna, R.

AU - Spada, S.

AU - Di Modugno, F.

AU - D'Andrea, D.

AU - Di Carlo, A.

AU - Panetta, M.

AU - Mileo, A.M.

AU - Sperduti, I.

AU - Antoniani, B.

AU - Gallo, E.

AU - Lawlor, R.T.

AU - Piemonti, L.

AU - Visca, P.

AU - Milella, M.

AU - Grazi, G.L.

AU - Facciolo, F.

AU - Chen, E.

AU - Scarpa, A.

AU - Nisticò, P.

N1 - Cited By :2 Export Date: 11 March 2021 CODEN: ERMEA Correspondence Address: Nisticò, P.; Tumor Immunology and Immunotherapy Unit, Italy; email: paola.nistico@ifo.gov.it Funding details: 1,000, 12182, IG 19822 Funding text 1: We thank all patients who donated samples for this study. We thank Giuliana Falasca, Maria Vincenza Sarcone and Vittoria Balzano for technical assistance. This work was supported by the Italian Association for Cancer Research AIRC: 5???1,000, 12182 (P.N., A.S.) and IG 19822 (P.N.). Synopsis image was created with BioRender.com (http://biorender.com/).

PY - 2020

Y1 - 2020

N2 - 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

AB - 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

KW - actin cytoskeleton

KW - AXL

KW - cancer-associated fibroblasts

KW - GAS6

KW - lung cancer

KW - AXL protein

KW - growth arrest specific protein 6

KW - hMENA protein

KW - regulator protein

KW - unclassified drug

KW - Article

KW - cancer associated fibroblast

KW - cancer prognosis

KW - cancer resistance

KW - cell interaction

KW - controlled study

KW - epithelial mesenchymal transition

KW - gene overexpression

KW - human

KW - human cell

KW - immune evasion

KW - intracellular signaling

KW - liquid chromatography-mass spectrometry

KW - lung non-small cell carcinoma cell line

KW - non small cell lung cancer

KW - pancreas adenocarcinoma

KW - pancreatic adenocarcinoma cell line

KW - priority journal

KW - protein function

KW - protein secretion

KW - proteomics

KW - regulatory mechanism

KW - tumor invasion

KW - tumor promotion

U2 - 10.15252/embr.202050078

DO - 10.15252/embr.202050078

M3 - Article

VL - 21

JO - EMBO Rep.

JF - EMBO Rep.

SN - 1469-221X

IS - 11

ER -