Abstract

In the tumor microenvironment, the stromal fibroblast population consists of subsets of cells that are activated and promote tumor initiation and growth. The factors that contribute to such selective activation of fibroblasts are not understood. Recent studies from our lab have highlighted the importance of cell mechanics in modulating the transcriptional response to signals from the microenvironment. In this study, we assessed the role of intrinsic cell geometric state in modulating fibroblast activation. To test this, we developed an engineered 3D fibroblast tumor co-culture system and used high resolution images to quantify multiple cell geometry sensitive nuclear morphological and chromatin organizational features. These features were then mapped to activation levels as measured by the nuclear abundance of transcription cofactor, MKL and protein levels of its target, αSMA. We observe the presence of activation-“primed” cell geometries that present higher activation levels which are further enhanced in the presence of cancer cells. Further we show that enriching the population of activation-primed cell geometric states by either increasing matrix rigidity or micro-patterning primed cell shapes results in increased efficiency of fibroblast activation. Collectively, these observations highlight the importance of cell mechanics in fibroblast activation within the heterogenous tumor microenvironment.