Resolving the mechanobiological interplay between androgen receptor signalling, microenvironment mechanics, cell mechanics, and metastatic prostate cancer progression

Clayton Molter

Regardless of mutational origin, in all cancers, cells must change their biophysical characteristics in order to migrate through fibrous multicellular environments. Softening of cancer cells’ actin cortex, cytoplasm, and nucleus, as well as increased contractility are emerging biomarkers of metastatic progression.  In addition to changes during cancer progression, cell mechanics are observed to do so as a function of microenvironment stiffness in the form of increased contractility. Prostate Cancer (PC) - a very common latent health hazard for men -appears to deviate from these cancer biophysics trends. In later stages, PC displays a transition to androgen-independence, accompanied by a drastic increase in invasiveness and metastatic potential. Critically, loss of androgen receptor (AR) is implicated in inducing PC invasiveness by initiating the epithelial-to-mesenchymal transition (EMT), which we have shown to amplify contractility. We anticipate that PC onset may lie in wait until key biochemical & biophysical cues create a “perfect storm” for metastasis progression, and we hypothesize that AR-signaling may be the critical factor facilitating the mechanical transitions required for PC metastasis.  In our work, we address this hypothesis by characterizing PC mechanics in response to substrate stiffness, metastatic progression, and in response to changes in AR-signalling and AR-expression. This is achieved by quantifying cell mechanics using a variety of established biophysical tools on cells adhered to elastic substrates spanning a range of physiological moduli to investigate the influence of microenvironment stiffness in conjunction with genetic and biochemical manipulations of AR-signalling and expression.  Through this work, we aim to resolve the mechanobiological interplay between AR-signalling, microenvironment mechanics, cell mechanics, and metastatic PC progression.

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