作者
Daniela Pankova, Yanyan Jiang, Maria Chatzifrangkeskou, Iolanda Vendrell, Jon Buzzelli, Anderson Ryan, Cameron Brown, Eric O'Neill
发表日期
2019/7/1
期刊
The EMBO journal
卷号
38
期号
13
页码范围
e100532
简介
Lung cancer remains the leading cause of cancer‐related death due to poor treatment responses and resistance arising from tumour heterogeneity. Here, we show that adverse prognosis associated with epigenetic silencing of the tumour suppressor RASSF1A is due to increased deposition of extracellular matrix (ECM), tumour stiffness and metastatic dissemination in vitro and in vivo. We find that lung cancer cells with RASSF1A promoter methylation display constitutive nuclear YAP1 accumulation and expression of prolyl 4‐hydroxylase alpha‐2 (P4HA2) which increases collagen deposition. Furthermore, we identify that elevated collagen creates a stiff ECM which in turn triggers cancer stem‐like programming and metastatic dissemination in vivo. Re‐expression of RASSF1A or inhibition of P4HA2 activity reverses these effects and increases markers of lung differentiation (TTF‐1 and Mucin 5B). Our study …
引用总数
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