uri physics colloquium

Development of biophysics-informed strategies in cancer therapeutics

Jonathan Celli, Ph.D.

Abstract

It is increasingly widely appreciated that tumor growth and progression are determined not only by the molecular biology and genetics of cancer cells but also by the physical properties of the tumor and surrounding tissues. In particular, the development of mechanically rigid fibrous stroma is a defining feature of many solid tumors and plays complex roles both promoting and constraining malignant growth behavior. It remains poorly understood however, how the tumor’s mechanical landscape, which is dynamically remodeled throughout progression and invasion, regulates susceptibilities to cancer therapeutics. Motivated by this background, several projects in our group examine how biophysical interactions with the tumor microenvironment impact upon phenotypic changes which determine therapeutic response. This work is enabled by the use of in vitro 3D tumor models with tunable and rheologically-characterized extracellular matrix (ECM). Combined with imaging-based analyses of phenotype and in situ microrheology measurements of local matrix remodeling, this platform provides a means to co-register rigidity-dependent cell shape, mechanics, and motility with response to therapeutic interventions. In this context we specifically contrast classical chemotherapy agents with photodynamic therapy (PDT), in which light activation of a photosensitizing molecular leads to cell death via local generation of reactive oxygen species. Interestingly, our recent results show that while modulation of ECM composition to promote increased motility/invasion imparts resistance to chemotherapy, the same chemoresistant populations exhibit increased sensitivity to PDT. Analysis of this and related findings will be discussed in the broader context of leveraging biophysical tools and analysis to inform cancer therapeutics.