期刊
ONCOGENE
卷 35, 期 40, 页码 5224-5236出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2016.57
关键词
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资金
- Comunidad de Madrid [S2010/BMD-2344/Colomics2]
- Juan de la Cierva programme
- Asociacion Espanola Contra el Cancer (AECC)
- ProteoRed contract
- Ministry of Economy and Competitiveness (MINECO)
- Comunidad de Madrid, 'Asociacion Espanola Contra el Cancer (AECC) [S2010/BMD-2344/Colomics2]
- MINECO [BIO2012-31023]
- Instituto de Salud Carlos III-FEDER [PRB2 (IPT13/0001-ISCIII-SGEFI/FEDER), RD12/0036/0041, RD12/0036/0021]
The transcription factor Twist1 is involved in the epithelial-mesenchymal transition and contributes to cancer metastasis through mostly unknown mechanisms. In colorectal cancer, Twist1 expression is mainly restricted to the tumor stroma. We found that human fibroblast cell lines stably transfected with Twist1 acquired characteristics of activated cancer-associated fibroblasts (CAFs), such as hyperproliferation, an increased ability to migrate and an alignment of the actin cytoskeleton. Further, Twist1-activated fibroblasts promoted increased matrix stiffness. Using quantitative proteomics, we identified palladin and collagen alpha 1(VI) as two major mediators of the Twist1 effects in fibroblast cell lines. Co-immunoprecipitation studies indicated that palladin and Twist1 interact within the nucleus, suggesting that palladin could act as a transcription regulator. Palladin was found to be more relevant for the cellular biomechanical properties, orientation and polarity, and collagen alpha 1(VI) for the migration and invasion capacity, of Twist1-activated fibroblasts. Both palladin and collagen alpha 1(VI) were observed to be overexpressed in colorectal CAFs and to be associated with poor colorectal cancer patient survival and relapse prediction. Our results demonstrate that Twist1-expressing fibroblasts mimic the properties of CAFs present at the tumor invasive front, which likely explains the prometastatic activities of Twist1. Twist1 appears to require both palladin and collagen alpha 1(VI) as downstream effectors for its prometastatic effects, which could be future therapeutic targets in cancer metastasis.
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