Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, 08036, Spain.
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA.
Cancer Lett. 2021 Jun 1;507:1-12. doi: 10.1016/j.canlet.2021.01.028. Epub 2021 Mar 6.
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.
大细胞癌（LCC）是一种罕见且侵袭性强的肺癌亚型，预后不良，且缺乏靶向治疗方法。源自 LCC 肿瘤的肿瘤相关成纤维细胞（TAFs）表现出过早衰老，而将肺成纤维细胞与 LCC 细胞系共培养则选择性地诱导成纤维细胞衰老，进而驱动 LCC 细胞的生长和侵袭。在这里，我们鉴定出 MMP1 在 LCC 细胞系中特异性过表达，并且我们表明 LCC 细胞中 MMP1 的表达对于在细胞培养和小鼠模型中诱导成纤维细胞衰老和随后的肿瘤促进是必需的。我们还表明，MMP1 与 TGF-β1 联合足以诱导成纤维细胞衰老和随后的 LCC 促进。此外，我们暗示 PAR-1 和氧化应激参与了 MMP1/TGF-β1 诱导的 TAF 衰老。我们的结果确立了 MMP1 在癌症中的全新作用，并支持基于靶向衰老 TAFs 的 LCC 新型治疗策略。
