Grant: Project Grant

Cancer cachexia is a syndrome that develops in many cancer patients and up to 80% of advanced cancers and is the direct cause of up to 30% of cancer deaths. Cachexia is characterized by weight loss and in particular muscle mass loss, and it makes cancer patients more frail and less able to receive the full-regimen of anti-cancer therapies. There are no approved medications to treat cachexia. While the cause of cancer cachexia remains largely unknown and likely involves many organ systems, it is believed that tumours produce factors that are released into the bloodstream that attack muscle cells. Skeletal muscle is made up of several cell types including stem cells that induce muscle repair after injury. In cachexia, muscle repair is impaired. In order to understand how tumour-secreted factors lead to impaired stem cell function, we identified other muscle cells that are responsive to the tumour-secreted factors and control muscle stem cell function. We identified fibro/adipogenic progenitor cells as primary targets. We also demonstrate that the tumour-derived factors induce changes in these cells, making them more inflammatory and unable to support muscle repair. Excitingly, we have also seen that exercise training can reverse many of these negative changes to fibro/adipogenic progenitors in several other conditions, including models of cancer survivorship. This project aims to fully characterize the negative changes to muscle fibro/adipogenic progenitors during the development of cachexia and how exercise may reverse these changes using transgenic mouse models, mouse models of cancer cachexia, models of exercise training and next-generation sequencing techniques. The research outputs from this project will identify negative changes to fibro/adipogenic progenitors as the first step in muscle wasting in the context of cachexia which will enable the development of new preventative strategies, including exercise training, for this incurable condition.