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

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-beta 1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-beta 1-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.

Automated summary

Large cell carcinoma (LCC) is a rare and aggressive subtype of lung cancer with poor prognosis and no targeted therapies. In this study, MMP1 has been identified as overexpressed in LCC cell lines and is shown to be necessary for induction of fibroblast senescence and consequent tumor promotion. The combination of MMP1 and TGF-beta 1 is sufficient to induce fibroblast senescence and LCC promotion, implicating PAR-1 and oxidative stress in this process. These results suggest a novel therapeutic strategy for LCC based on targeting senescent TAFs.