Insights into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma.

Insights into Fibroblast Plasticity: CCN2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma. Am J Pathol. 2019 Oct 11;: Authors: Tsang M, Quesnel K, Vincent K, Hutchenreuther J, Postovit LM, Leask A Abstract Tumor stroma resembles a fibrotic microenvironment, being characterized by the presence of myofibroblast-like cancer-associated fibroblasts (CAFs). In wild-type mice injected with melanoma cells, we show that the stem cell transcription factor Sox2 is expressed by tumor cells and induced in CAFs derived from synthetic fibroblasts. These fibroblasts were labeled postnatally with green fluorescent protein using mice expressing a tamoxifen-dependent Cre recombinase under the control of a fibroblast-specific promoter/enhancer. Conversely, fibroblast activation was impaired in mice with a fibroblast-specific deletion of Ccn2, associated with reduced expression of alpha-smooth muscle actin and Sox2. Multipotent Sox2-expressing skin-derived precursor (SKP) spheroids were cultured from murine back skin. Using lineage tracing and flow cytometry, approximately 40% of SKPs were found to be derived from a Col1a2 origin and acquired multipotency in culture. Inhibition of mechanotransduction pathways prevented myofibroblast differentiation of SKPs and expression of Ccn2. In SKPs deleted for Ccn2, differentiation into a myofibroblast, but not an adipocyte or neuronal phenotype, was also impaired. In human...
Source: The American Journal of Pathology - Category: Pathology Authors: Tags: Am J Pathol Source Type: research