Mechanistic study of skeletal muscle proteolysis induced by breast cancer-secreted extracellular vesicles

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PROJECT SUMMARY/ABSTRACT Skeletal muscle loss and weakness are a key part of cancer cachexia and are associated with poor clinical outcomes and a poor quality of life in cancer patients. Despite previous advances in understanding the mechanisms of cancer cachexia, little is known about how the presence of breast cancer influences skeletal muscle, and no early detection method or therapy currently exists for cancer-associated muscle loss and cachexia. The proposed project will investigate this unique aspect of tumor–host crosstalk from the novel perspective of cancer-secreted extracellular vesicles (EVs), whose function in transferring cancer-derived signals to various types of normal cells has been recently recognized. The goal of this study is to identify the mechanisms by which breast cancer-secreted EVs dysregulate skeletal muscle mass and function. We will test the novel hypothesis that miRNA and protein cargo of cancer-secreted EVs induce muscle protein degradation by activating the calcium-dependent calpain proteases and the ubiquitin-proteasome system. In Aim 1, we will first determine how selected miRNA cargo of breast cancer-secreted EVs dysregulate calcium transport in muscle cells to activate calpains and promote muscle protein breakdown. Using mouse models, we will evaluate to what extent this mechanism contributes to cancer-associated muscle mass loss and dysfunction. Next, we will identify the mechanism through which breast cancer-secreted EVs stimulate macrophages to induce skeletal muscle inflammation and how this activates the ubiquitin-proteasome system to promote protein degradation. The role of macrophages and inflammatory cytokines will be determined using mouse models. In Aim 2, we will assess the beneficial effects of potential therapeutics targeting EV-mediated mechanisms on skeletal muscle. Experimental therapeutic approaches will be assessed individually or in combination in mouse models for the efficacy in protecting muscle from the devastating effect of selected EV cargo effectors. The therapeutics will be administered before or after cancer-associated skeletal muscle loss is detected, to assess their performance in the prevention and treatment settings. In Aim 3, we will analyze blood samples and computed tomography scan images from breast cancer patients, to assess the associations between selected EV cargo molecules and parameters of skeletal muscle loss. The proposed study will provide a new understanding of the distant effects of cancer on skeletal muscle. It will also establish rationales for novel therapeutic strategies to prevent or treat cancer-associated muscle loss and cachexia, which would improve the quality of life in cancer patients by restoring muscle function and indirectly improve anticancer treatment response towards our long-term objective to deliver better cancer care and achieve better results for patients.