Diabetes Mellitus Promotes Breast Tumor Progression via Glycation Mediated Matrix Stiffening

PROJECT SUMMARY/ABSTRACT Diabetes mellitus is a complex disease associated with hyperglycemia. A growing body of epidemiological evidence supports that patients with comorbidity of diabetes mellitus and breast cancer are at a greater risk of poor prognosis and death compared with non-diabetic patients. However, the interplay between tumor

progression and diabetes is still mechanistically unclear. Hyperglycemia results in glycation within the tumor extracellular matrix (ECM), where sugars crosslink collagen through a non-enzymatic reaction resulting in increased matrix stiffness. Notably, ECM stiffness is correlated with metastatic and promotes malignancy of

tumors through multiple aspects, such as promoting proliferation and epithelial-mesenchymal transition (EMT). ECM stiffness also regulates endothelial cells, as our lab has shown previously that ECM stiffness promotes tumor angiogenesis and damages vascular integrity. Malformed and hyper-permeable vasculature is a hallmark

of breast tumors and is known to lead to more metastasis and a more aggressive tumor phenotype. Noting the carcinogenic effect of glycation and the association between diabetes and tumor progression, my study aims to understand the mechanism by which diabetic hyperglycemia promotes breast tumor progression via glycation-

mediated matrix stiffening. I have recently established a murine model where hyperglycemia was induced prior to tumorigenesis. With this model, I find that hyperglycemia increases tumor growth, tumor stiffness, advanced glycation end-product (AGEs) concentration, and EMT of tumor cells. Upon treating diabetic mice with glycation

inhibitors, I observed a reduction of the previously tested metrics in diabetic tumors to levels comparable with non-diabetic tumors. These findings describe a novel mechanism by which diabetic hyperglycemia promotes breast tumor progression and provide evidence that glycation inhibition is a potential adjuvant therapy for diabetic

cancer patients due to its key role of matrix stiffening in both diseases. In the F99 phase of this application, these findings will be extended by determining the mechanisms by which glycation-mediated ECM stiffening activates tumor angiogenesis (Aim 1). Noting that glycation stiffens ECM and produces AGEs which initiate cell signaling

through RAGE receptors. AGE-RAGE signaling has been implicated in angiogenic behavior. A particular emphasis will thus be to tease apart the effect of AGE-RAGE signaling and matrix stiffening on tumor angiogenesis. Macrophage-involved chronic inflammation is emerging as a link between diabetes and breast

cancer. My preliminary data show that there are more M2 macrophages within stiffer tumors. Thus, in the K00 phase (Aim 2), a research/training environment will be sought to examine the mechanism by how glycation- mediated ECM stiffening promotes tumor progression via increasing tumor immune cell infiltration and

influencing immune cell behaviors. The ultimate goal of my studies will be to provide a more holistic understanding of how diabetic hyperglycemia influences tumor progression and to serve as a basis for future therapeutic intervention.