Targeting the crosstalk of lipid and glucose metabolism to stop cancer-associated wasting

ongoing

Cachexia is the deadly outcome of many late stage cancers. It is characterized by severe wasting of adipose tissue and muscle mass, cardiac dysfunction and systemic inflammation. To date, no prognostic biomarker or efficient treatment against wasting is available, and ultimately 30% of all patients with cancer will die of cachexia. Hence, we have the critical unmet and urgent medical need of developing novel biomarkers and treatment options. Until now, research has focused on targeting either tumor-derived secreted proteins or specific aspects of organ dysfunction such as muscle atrophy. StopWaste builds on recent advances of my group in targeting adipose tissue malfunction in cachexia. My current data support the new concept that tumors activate futile substrate cycling in adipocytes, which leads to an energy crisis that drives systemic metabolic dysfunction. Interestingly, similar to obesity, perturbed adipose tissue in cachexia causes the increased release of bioreactive signaling lipids such as C16:0 ceramides which appear before any wasting occurs. My recently established state-of-the-art multi-omics workflow to trace substrate cycling paired with the functional and clinical readouts of cachexia present in my lab now enable me to identify the molecular origin of these cycles and their impact on systemic metabolism. Using my established cell culture systems and multiple cachexia mouse models as well as patient samples, I will investigate (1) the origin of the altered circulating lipids and their potential as early cachexia biomarkers, (2) if they derive from perturbed adipocytes by futile cycling, and (3) if they drive insulin resistance which, in combination with the as-yet unknown tumor-islet axis I have identified, aggravates catabolism by lack of insulin anabolic signaling. In summary, StopWaste addresses the interplay of glucose and lipid metabolic pathways that lead to cachexia, providing for the first time a holistic signature of wasting metabolism.