Biophysico-Computational Perspective of Breast Cancer Pathogenesis and Treatment Response

摘要

The extracellular matrix (ECM) regulates breast homeostasis and is corrupted in breast cancers. We showed that the breast ECM progressively reorganizes into large bundles and stiffens due to high activity of ECM remodeling and cross-linking enzymes such as lysyl oxidase (LOX). The functional relevance of this was revealed through in vitro and in vivo work which revealed that ECM stiffness enhances breast cell growth, survival, migration and regulates treatment responsiveness by promoting integrin adhesions and signaling to enhance tumorigenesis and metastasis and compromise treatment efficacy. More recently, we also found that ECM stiffness induces inflammation and angiogenesis and we are exploring how this effect may regulate metastasis and treatment response by determining if this is mediated through direct effects on vascular endothelial cells and immune cells or indirectly by modulating growth factor and chemokine levels. To clarify how ECM remodeling modulates breast cell survival we identified a novel mechanism elicited through ECM dimensionality and that promotes Arf6-dependent breast cell survival. We are now exploring the clinical relevance of these findings through a comprehensive molecular and biophysical characterization of freshly excised human breast tissues.