Project 458850

Regardless of mutational origin, in all cancers, cells must change their biophysical characteristics to migrate through fibrous multicellular environments. As such, cell softening and increased cell-generated forces are emerging near-universal biomarkers of metastatic progression. In addition to mechanical changes during cancer progression, cancerous cells pull harder in stiffer local environments as found in tumour tissues. Prostate Cancer (PC) - a very common latent health hazard for men - appears to deviate from these cancer biophysics trends, suggesting another factor in play related to androgens. Initially, PC growth is androgen-dependent, which has motivated androgen deprivation as a therapeutic strategy; however, in later stages PC becomes androgen-independent, accompanied by a drastic increase in invasiveness and metastatic potential. Critically, the loss of androgen receptors (ARs) is implicated in inducing PC invasiveness by initiating the epithelial-to-mesenchymal transition, which we have shown increases cell forces. I hypothesize that AR-signaling may be the critical factor facilitating the mechanical transitions required for PC metastasis. In the proposed project, I will address this hypothesis by characterizing the mechanics of variably metastatic PC cell lines in response to substrate stiffness and in response to changes in AR-signalling and expression. I will achieve this by quantifying cell mechanics using several established biophysical tools on cells adhered to substrates spanning a range of physiological stiffnesses in conjunction with genetic and biochemical manipulations of AR-signalling and expression. Through this work, I aim to resolve the mechanobiological interplay between AR-signalling, microenvironment mechanics, cell mechanics, and metastatic PC progression. This mechanistic interdisciplinary understanding will offer new strategies in PC diagnostics and potential therapeutics not forthcoming from traditional biochemical approaches.