Twist1-induced activation of human fibroblasts promotes matrix stiffness by upregulating palladin and collagen α1(VI).

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 α1(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 α1(VI) for the migration and invasion capacity, of Twist1-activated fibroblasts. Both palladin and collagen α1(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 α1(VI) as downstream effectors for its prometastatic effects, which could be future therapeutic targets in cancer metastasis.

Genomic organization and control of the grb7 gene family.

Grb7 and their related family members Grb10 and Grb14 are adaptor proteins, which participate in the functionality of multiple signal transduction pathways under the control of a variety of activated tyrosine kinase receptors and other tyrosine-phosphorylated proteins. They are involved in the modulation of important cellular and organismal functions such as cell migration, cell proliferation, apoptosis, gene expression, protein degradation, protein phosphorylation, angiogenesis, embryonic development and metabolic control. In this short review we shall describe the organization of the genes encoding the Grb7 protein family, their transcriptional products and the regulatory mechanisms implicated in the control of their expression. Finally, the alterations found in these genes and the mechanisms affecting their expression under pathological conditions such as cancer, diabetes and some congenital disorders will be highlighted.