Cardiac Calcium in Cancer Cachexia

Cancer cachexia is a severe wasting condition that leads to substantial loss of skeletal and even heart muscle in many patients with advanced cancer. It is not simply a consequence of reduced nutrition but results from profound changes in metabolism and energy balance. Cachexia is a major cause of weakness, poor quality of life, and eventually death in cancer patients. One molecule strongly associated with this condition is interleukin-6 (IL-6), an inflammatory signal released by tumours. Elevated levels of IL-6 have been linked to the severity of cachexia, but the exact mechanisms through which it causes muscle wasting, especially in the heart, are still not well understood. This project aims to uncover how IL-6 and other molecules act directly on the heart to trigger muscle wasting and metabolic alterations. We hypothesize that IL-6 activates specific signalling pathways in heart muscle cells, leading to an increase in the activity of a calcium-regulating protein called SERCA (sarcoplasmic reticulum Ca ATPase). Enhanced SERCA activity could make heart cells consume more energy (ATP) than normal, resulting in higher energy expenditure. Over time, this energy imbalance may contribute to the breakdown and atrophy of heart tissue. To test this hypothesis, we will employ a combination of advanced laboratory techniques and appropriate animal models. These include studying calcium handling in heart muscle cells using electrophysiology and confocal microscopy, measuring ATP levels and metabolic activity, and assessing heart and vessel function in mice through echocardiography, PET/CT imaging and myography. We will also apply state-of-the art genetic approaches such as CRISPR/Cas9 and shRNA to block IL-6 or its signalling components, and we will perform RNA sequencing and protein analyses to identify the downstream effects in the heart. Our findings will be further validated in a melanoma model of cancer cachexia, in both male and female mice, and further compared with data from cancer patients. Importantly, we will test whether blocking IL-6 signalling using olamkicept, a drug that inhibits IL-6 trans-signalling, can prevent or mitigate the development of cardiac atrophy in the context of cancer cachexia. This research is innovative because it proposes that the hearts response to tumour-derived cytokines leads to increased energy demand as a primary cause of muscle wasting. Understanding this mechanism could provide new insights not only into cancer-associated cachexia but also into other diseases involving cytokine-mediated muscle loss. In the long term, our results may help identify new treatment strategies to preserve muscle mass and function and improve survival and quality of life for patients with cancer. The study will be carried out by Dr. Xaver König and Dr. Attila Kiss, in close collaboration with national and international partners who will contribute specialized expertise in cardiovascular physiology, molecular biology, and metabolic analysis.