@article{1810c91cdac8436398d6289705602676,
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",
note = "Funding Information: We thank Sara Ozcoz, Raquel Bermudo, {\`E}lia Alca{\~n}iz, N{\'u}ria de la Iglesia (IDIBAPS), Federica Facchinetti and Giuliana Pollaci (IRCCS) and Elisabet Urrea (UB) for technical assistance, Manuel Serrano (IRB), Hidetoshi Mori (UC Davis) and Joan Montero (IBEC) for helpful discussions, and Daniel Navajas and Ramon Farr{\'e} (UB) for support. This work was further supported by grants from the Agencia Estatal de Investigaci{\'o}n (AEI/FEDER) (PI13/02368, SAF2016-79527-R and PID2019-110944RB-I00 (AEI/ 10.13039/501100011033) to JA, PI16/00890 to NR), Fundaci{\'o} Privada Cellex (to JA), National Institutes of Health (grant R01 GM132100 to ER), Generalitat de Catalunya (AGAUR SGR661 and CERCA Programme to JA), Junta Provincial de Barcelona de l'Associaci{\'o} Espanyola Contra el C{\`a}ncer (AECC-B16-917 to JA), Italian Ministry of Health (RF-2016-02362946 to LR), Italian Association for Cancer Research (AIRC-IG21431 to LR), Sociedad Espa{\~n}ola de Neumolog{\'i}a y Cirug{\'i}a Tor{\'a}cica – SEPAR (SEPAR 437 to NR), COST Action (PROTEOSTASIS BM1307), and by fellowships from Ci{\^e}ncia sem Fronteiras CNPq (to RI), and Universitat de Barcelona/beca APIF (to PD). Funding Information: We thank Sara Ozcoz, Raquel Bermudo, {\`E}lia Alca{\~n}iz, N{\'u}ria de la Iglesia (IDIBAPS), Federica Facchinetti and Giuliana Pollaci (IRCCS) and Elisabet Urrea (UB) for technical assistance, Manuel Serrano (IRB), Hidetoshi Mori (UC Davis) and Joan Montero (IBEC) for helpful discussions, and Daniel Navajas and Ramon Farr{\'e} (UB) for support. This work was further supported by grants from the Agencia Estatal de Investigaci{\'o}n (AEI/ FEDER ) ( PI13/02368, SAF2016-79527-R and PID2019-110944RB-I00 (AEI/ 10.13039/501100011033) to JA, PI16/00890 to NR), Fundaci{\'o} Privada Cellex (to JA), National Institutes of Health (grant R01 GM132100 to ER), Generalitat de Catalunya ( AGAUR SGR 661 and CERCA Programme to JA), Junta Provincial de Barcelona de l{\textquoteright}Associaci{\'o} Espanyola Contra el C{\`a}ncer (AECC- B16-917 to JA), Italian Ministry of Health (RF-2016-02362946 to LR), Italian Association for Cancer Research (AIRC- IG21431 to LR), Sociedad Espa{\~n}ola de Neumolog{\'i}a y Cirug{\'i}a Tor{\'a}cica – SEPAR (SEPAR 437 to NR), COST Action (PROTEOSTASIS BM1307), and by fellowships from Ci{\^e}ncia sem Fronteiras CNPq (to RI), and Universitat de Barcelona /beca APIF (to PD). Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = jun,
day = "1",
doi = "10.1016/j.canlet.2021.01.028",
language = "English (US)",
volume = "507",
pages = "1--12",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
}