Linking Mechanosensation and Cancer Progression in the Hyperglycemic Extracellular Matrix RESUBMISSION - PROJECT SUMMARY Glycation is a chemical process whereby free sugars are added non-enzymatically to biological macromolecules, facilitating cancer-promoting processes ranging in scope from DNA misassembly to tissue failure. In a state of uncontrolled diabetes-induced hyperglycemia, advanced glycation end-products (AGEs) can crosslink matrix proteins, preventing matrix turnover while increasing tissue stiffness. Risk of breast cancer increases in patients exhibiting type 2 diabetic hyperglycemia due to a variety of factors not limited to insulinemic inflammation, metabolic regulation by glucose signaling, and confounding behavioral or socioeconomic factors. AGEs can also directly bind the receptor for AGEs (RAGE) to increase cytokine secretion and promote an innate pathological inflammatory response. The extent of mechanical signaling to epithelial cells by glycation is still unknown, though enzymatic tissue crosslinking in diabetic patients has been targeted in clinical trials. Thus, it is of significant interest to the cancer biology field to determine the impact of AGEs on tumor progression in a matrix-specific context, as the extent of this relationship will inform future therapy development. The extracellular matrix (ECM) is significantly stiffer than normal tissue in many cancers, and elevated matrix stiffness has been shown to promote metastasis; prior work in my lab has shown both in vitro and in vivo that increased matrix crosslinking, resulting in a stiffer matrix, causes a tumor-associated vascular phenotype. Additionally, we have recently shown that tumor burden is increased in hyperglycemic mice, an effect which can be ablated by reversing AGE crosslinking in vivo. My data indicate that glycation-induced stiffness increases proliferative signaling, a hallmark of cancer, and that hyperglycemic tumors progress quicker with greater expression of mesenchymal markers than is seen in control tumors, even when RAGE expression is silenced. Given these findings, I will use two immunocompetent models for metastasis, and recellularized biomaterials ex vivo, to investigate the hypothesis that glycation causes specific modifications to the tumor ECM that produce a malignant phenotype independent of secreted signaling factors. In aim 1, diabetes-related crosslink species will be quantified and the specific contribution of the diabetic ECM to cancer progression and metastasis will be investigated. In aim 2, the role of RAGE inflammation on cancer progression will be explored. This work will implicate hyperglycemia in priming breast cancer for metastasis via crosslink initiation, and drive therapeutic targeting of AGEs.
