Grant: Project Grant

It is well-documented that tumor cells can secrete numerous signalling factors that affect distant normal tissues. For example, tumor-secreted inflammatory factors can initiate muscle or fat tissue breakdown into protein or fatty acids, respectively, that can be used to feed the growing tumor, but consequently can severly decrease the weight of cancer patients. What remains incompletely understood is if tumor-secreted factors (TSFs) can initiate a signalling cascade in the heart, rendering cardiomyocytes (the contractile cells of the heart) susceptible to cell death when treated with anti-cancer drugs. Understanding the role of TSFs on the heart is important clinically, because it is now known that a high percentage of cancer patients develop heart failure as a direct consequence of their cancer therapy. In this proposal we describe a novel signalling pathway where tumor secreted nucleosides (the precursors for generating DNA in the cell and required for cells to duplicate) can circulate in the serum of cancer mice or patients and bind and activate a specific receptor on heart cells. We propose that activation of this heart receptor can initiate a unique signalling pathway that makes heart cells vulnerable to cell death. Thus, in the presence of cancer therapies (that are known to cause heart failure in cancer patients) we observe significant heart cell death when this signalling pathway is activated. This proposal has identified a new signalling pathway where the tumor can have a direct signalling effect on the heart, making it susceptible to cancer therapy-mediated death (and subsequently heart failure). This project has direct implications for cancer patients, as it may identify a new biomarker that could predict which cancer patients will be more prone to developing heart failure as a direct consequence of their TSFs and cancer treatment, but also provide a new therapeutic target that may prevent the development of cancer therapy-mediated heart failure.