Roles of collagen crosslinking and ECM remodeling in mammary tumor malignant transformation

In vivo, cells are maintained in mechanical balanced microenvironments.  We showed that ECM stiffness alters cell proliferation, survival and polarity via integrin clustering, focal adhesion maturation, and cell-generated force.  Increased tissue stiffness, changes of ECM (e.g. collagen) remodeling and ECM remodeling enzymes (such as MMPs, lysyl oxidase LOX) are strongly associated with breast cancer progression.  We therefore hypothesis ECM remodeling affects tumor progression via increasing tissue stiffness.  Since crosslinking of collagen I increases its mechanical strength, we tested if collagen crosslinking by Lysyl Oxidase (LOX) affects tumor progression. We have shown that breast transformation is accompanied by elevated levels LOX, collagen I deposition, and significant collagen cross-linking as well as a pronounced stiffening of the breast and its surrounding extracellular matrix. We tested and confirmed ECM stiffness can modulate PTEN level and PI3K activity in the culture system. Thus, collagen crosslinking and substrate stiffness can modulate oncogene effects through PTEN and integrin dependent pathways and thus affect breast cancer progression. To this end we employ three dimensional organotypic culture models, xenograft and syngeneic mouse models, transgenic animals and fresh and fixed clinical samples.