Grant: CIHR - ICR / Cancer Research Society Partnership - Research Grants

I. BACKGROUND. Increasing global incidence of obesity has highlighted the role of fat cells in cancer progression. Obese breast and ovarian cancer patients exhibit more aggressive tumors and disease progression is markedly faster. In breast cancer, fat cells are the most abundant and active component of the breast tumour microenvironment (TME). Recently, numerous studies have shown that adipocytes and their progenitor cells promote breast cancer aggressiveness by stimulating proliferation and invasion. Ovarian cancers are largely detected in advanced stages when the tumour has already preferentially metastasized to the omentum, a major site of abdominal fat. Adipocytes are well known for maintaining tissue architecture, providing a source of energy, and participating in endocrine processes; however their involvement in cancer development, progression, metastasis, and response to therapy is just beginning to unfold. Moreover, the effect of fat cells on cancer cell responses to therapeutic treatment remains poorly explored. Recent reports indicate that human adipose tissue may contribute to resistance of cancer cells to various chemotherapeutic and anti-angiogenic drugs. These studies provide accumulating evidence for the activation of survival mechanisms in tumor cells due to crosstalk with surrounding adipose tissue and it is conceivable that such TME also modulates the effects of other anti-cancer therapeutics like immunotherapies. Oncolytic viro-immunotherapy (OV) has emerged as a novel therapeutic for the treatment of cancer. Our laboratory is currently investigating how the TME, which contains a diverse population of cells including cancer-associated fibroblasts, cancer-associated adipocytes (CAAs), vascular endothelial cells, immune cells and the extracellular matrix that binds them together, impact virus-based immunotherapies. The project proposed herein builds upon preliminary studies performed in our laboratory that have evaluated the efficacy of OV therapy in breast cancer tumour models where the tumour is grown subcutaneously or in the fat-pad of high-fat diet-induced obesity or normal diet mice. This work showed that tumours developed in “fatty” environments are significantly less sensitive and responsive to virotherapy. In vitro, ovarian or breast cancer cell culture in adipocyte conditioned media led to a decrease in virus replication and OV-induced cell death in a panel of diverse OV platforms. The overarching goal of this project is to unveil and dissect how the interplay of cancer-associated adipocytes and cancer cells influence OV responses in the tumour niche. II. RATIONALE: We propose that CAAs not only modulate tumour development, progression, metastasis, but also induce resistance to virus-based anti-cancer therapies in tumours enriched in fat cells, such as breast and ovarian cancers. Adipocyte-released bioactive molecules (i.e. lipids) can confer OV-resistance. We will test this model by addressing two aims: AIM 1. Characterize the nature of the crosstalk between CAAs and cancer cells that inhibits virotherapy. AIM 2. Determine the role of CAA on OV resistance in-vivo. Orthotopic syngeneic breast and ovarian cancer mouse models will be used to evaluate the role of adipocytes and their secreted products in virotherapy resistance. III. RELEVANCE: Understanding and harnessing the crosstalk between cancer cells in CAAs would allow the optimization of the next generation of OV therapy for tumous grown in “fatty” microenvironments.