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

Research output: Contribution to journalArticlepeer-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 languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalCancer Letters
Volume507
DOIs
StatePublished - Jun 1 2021

Keywords

  • Cancer-associated fibroblasts
  • MMP1
  • TGF-β
  • lung cancer
  • senescence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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