Grant: DRA: Canada Impact+ Research Training Awards - Doctoral

"Metastatic melanoma remains a major clinical challenge. Known therapies that block cancer cell overgrowth and boost the immune system attack on cancer cells can be effective, but lasting effects are limited as tumors can to remodel their microenvironment to create a stiff, fibrotic extracellular matrix (ECM). This fibrotic tissue is a product of cancer-associated collagen-producing cells (fibroblasts) which foster tumor growth, increase drug resistance, and hinder immune cell infiltration. In parallel, treatment may cause hypoxia (low oxygen) that can drive uncontrolled blood vessel growth. Together, these hinder treatment effectiveness, warranting novel strategies that directly target biological activities in the stroma (noncancerous supportive tissues). This proposal focuses on the CCN family of ECM proteins that modify cellular responses to signals that promote stress, such as hypoxia. CCN1/CCN2 drive fibrosis and blood vessel formation, conversely CCN3 acts reciprocally and is antifibrotic. In human melanoma patients, elevated CCN1/CCN2 levels and reduced levels of CCN3 are associated with drug resistance and poorer survival. BLR-200 is a CCN3- based peptide showing preliminary promise for reducing fibrosis and abnormal blood vessel growth, with a trend toward limiting tumor growth. Using an established mouse model and immunohistochemical and single-cell RNA sequencing approaches, I will test whether BLR-200 blocks (1) blood vessel formation and ECM deposition in and around tumors and (2) activation of cells –ECM-producing fibroblasts - within the tumor microenvironment. These studies will provide evidence that BLR-200 can restore CCN3-like activity and modify the tumor stroma’s response to be more receptive to drug treatments, thereby improving patient survival."