Biology

Dr. Shamik Sen
Dept. of Biosciences and Bioengineering, IIT Bombay

Abstract:

Tumors are comprised of phenotypically distinct sub-populations, with heterogeneity associated with higher tumor growth and poor therapeutic efficiency. However, due to difficulty associated with measuring phenotypic variability, most studies on tumor heterogeneity have focused on genetic heterogeneity, but not on phenotypic heterogeneity. Here, we first quantify heterogeneity in cell size and deformability in breast cancer cells. Using a multiscale stochastic computational model which accounts for this experimentally observed heterogeneity, we show that combined heterogeneity in cell size and deformability enhances cancer invasiveness, with highest invasiveness at intermediate cell-cell adhesion. Using publicly available single cell RNAseq data of breast cancer samples, comparison of functional level heterogeneity with transcript-level heterogeneity revealed wide variation in expression of the mechanoresponsive protein a-actinin-4. We then show that a-actinin-4 regulates invasion by modulating expression of non-muscle myosin IIB and localization of non-muscle myosin IIA. In addition to highlighting the importance of biophysical heterogeneity on cancer invasion, we demonstrate the importance of the actomyosin cytoskeleton in regulating cancer invasion via modulation of MMP activity and mediating nuclear deformation.