MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence

Marta Gabasa; Evette S. Radisky; Rafael Ikemori; Giulia Bertolini; Marselina Arshakyan; Alexandra Hockla; Paula Duch; Ornella Rondinone; Alejandro Llorente; Maria Maqueda; Albert Davalos; Elena Gavilán; Alexandre Perera; Josep Ramírez; Pere Gascón; Noemí Reguart; Luca Roz; Derek C. Radisky; Jordi Alcaraz

doi:10.1016/j.canlet.2021.01.028

MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence

Marta Gabasa, Evette S. Radisky, Rafael Ikemori, Giulia Bertolini, Marselina Arshakyan, Alexandra Hockla, Paula Duch, Ornella Rondinone, Alejandro Llorente, Maria Maqueda, Albert Davalos, Elena Gavilán, Alexandre Perera, Josep Ramírez, Pere Gascón, Noemí Reguart, Luca Roz, Derek C. Radisky, Jordi Alcaraz

Cancer Biology

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

Abstract

Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models. We also show that MMP1, in combination with TGF-β1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-β1-induced TAF senescence. Our results establish an entirely new role for MMP1 in cancer, and support a novel therapeutic strategy in LCC based on targeting senescent TAFs.

Original language	English (US)
Pages (from-to)	1-12
Number of pages	12
Journal	Cancer Letters
Volume	507
DOIs	https://doi.org/10.1016/j.canlet.2021.01.028
State	Published - Jun 1 2021

Keywords

Cancer-associated fibroblasts
MMP1
TGF-β
lung cancer
senescence

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.canlet.2021.01.028

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Gabasa, M., Radisky, E. S., Ikemori, R., Bertolini, G., Arshakyan, M., Hockla, A., Duch, P., Rondinone, O., Llorente, A., Maqueda, M., Davalos, A., Gavilán, E., Perera, A., Ramírez, J., Gascón, P., Reguart, N., Roz, L., Radisky, D. C., & Alcaraz, J. (2021). MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence. Cancer Letters, 507, 1-12. https://doi.org/10.1016/j.canlet.2021.01.028

Gabasa, M, Radisky, ES, Ikemori, R, Bertolini, G, Arshakyan, M, Hockla, A, Duch, P, Rondinone, O, Llorente, A, Maqueda, M, Davalos, A, Gavilán, E, Perera, A, Ramírez, J, Gascón, P, Reguart, N, Roz, L, Radisky, DC & Alcaraz, J 2021, 'MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence', Cancer Letters, vol. 507, pp. 1-12. https://doi.org/10.1016/j.canlet.2021.01.028

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title = "MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence",

abstract = "Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models. We also show that MMP1, in combination with TGF-β1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-β1-induced TAF senescence. Our results establish an entirely new role for MMP1 in cancer, and support a novel therapeutic strategy in LCC based on targeting senescent TAFs.",

keywords = "Cancer-associated fibroblasts, MMP1, TGF-β, lung cancer, senescence",

author = "Marta Gabasa and Radisky, {Evette S.} and Rafael Ikemori and Giulia Bertolini and Marselina Arshakyan and Alexandra Hockla and Paula Duch and Ornella Rondinone and Alejandro Llorente and Maria Maqueda and Albert Davalos and Elena Gavil{\'a}n and Alexandre Perera and Josep Ram{\'i}rez and Pere Gasc{\'o}n and Noem{\'i} Reguart and Luca Roz and Radisky, {Derek C.} and Jordi Alcaraz",

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doi = "10.1016/j.canlet.2021.01.028",

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T1 - MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence

AU - Gabasa, Marta

AU - Radisky, Evette S.

AU - Ikemori, Rafael

AU - Bertolini, Giulia

AU - Arshakyan, Marselina

AU - Hockla, Alexandra

AU - Duch, Paula

AU - Rondinone, Ornella

AU - Llorente, Alejandro

AU - Maqueda, Maria

AU - Davalos, Albert

AU - Gavilán, Elena

AU - Perera, Alexandre

AU - Ramírez, Josep

AU - Gascón, Pere

AU - Reguart, Noemí

AU - Roz, Luca

AU - Radisky, Derek C.

AU - Alcaraz, Jordi

PY - 2021/6/1

Y1 - 2021/6/1

N2 - Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models. We also show that MMP1, in combination with TGF-β1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-β1-induced TAF senescence. Our results establish an entirely new role for MMP1 in cancer, and support a novel therapeutic strategy in LCC based on targeting senescent TAFs.

AB - Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models. We also show that MMP1, in combination with TGF-β1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-β1-induced TAF senescence. Our results establish an entirely new role for MMP1 in cancer, and support a novel therapeutic strategy in LCC based on targeting senescent TAFs.

KW - Cancer-associated fibroblasts

KW - MMP1

KW - TGF-β

KW - lung cancer

KW - senescence

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MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence

Abstract

Keywords

ASJC Scopus subject areas

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