Evaluating the role of the tumor macroenvironment in cancer cachexia

Project Summary Cancer cachexia is a severe metabolic syndrome characterized by muscle and adipose wasting. It is a significant complication faced by cancer patients that reduces quality of life, limits treatment efficacy, and accounts for nearly a third of a third of cancer-associated deaths. Despite its prevalence, cancer cachexia remains untreatable by current conventional means, as its complex multi-organ etiology is poorly understood. Cachexia involves dysregulated crosstalk between the tumor, the tumor microenvironment (TMiE), and organs essential for energy homeostasis including muscle, adipose, the liver, and the brain. Thus, examination of the broader tumor macroenviornment (TMaE) is critical. Using pancreatic cancer as a model system, this proposal aims to elucidate the mechanisms by which cancer cells and the TMiE coordinate with the TMaE to drive cachexia, thereby identifying novel therapeutic targets for intervention. In the F99 phase, I will investigate the tumor-TMiE interaction focusing on how tumor-associated macrophages (TAMs) contribute to muscle and adipose wasting. I have shown that TAMs potentiate muscle atrophy via tumor necrosis factor weak inducer of apoptosis (TWEAK) signaling 1 . My current investigation suggests pancreatic cancer cells recruit and instruct TAMs to secrete a well-known metabolic regulator, known as Growth and Differentiation Factor 15 (GDF15), which acts on the hindbrain receptor GFRAL to accelerate cachexia. Specifically, this is carried out via a cancer cell-derived Colony Stimulating Factor 1 (CSF1 )-dependent mechanism. Genetic manipulation of both CSF1 and GDF15 successfully modulated cachexia phenotypes in our models. These findings suggest that targeting TAM-mediated signaling pathways can mitigate cachexia. The proposed experiments in the F99 phase will assess this therapeutic opportunity. In the KOO phase, I will expand the focus to liver-mediated pathways in cachexia. Like the nervous system, the liver plays a central role in systemic energy homeostasis. During the early phases of cancer progression, tumor-secreted factors prime the liver for metastasis. I will address whether early established metastatic priming events can drive the onset of cancer cachexia. This aim will utilize advanced animal models and metabolic assays to assess liver dysfunction as an early driver of cachexia. This work will provide a multi-organ perspective on cancer cachexia, unveiling the complex signaling network involving tumor cells tumor, the TMiE, and the TMaE. The insights from this research will not only enhance our understanding of cancer cachexia etiology but also identify potential targets for intervention, ultimately improving the survival and quality of life of cancer patients.