Cachexia associated with pancreatic ductal adenocarcinoma (PDAC) is correlated with shorter survival, reduced efficacy of chemotherapy and surgery, and a reduction in quality of life. PDAC is the third leading cause of cancer-related death in the US with a 5-year survival rate <10%. Cachexia is a common complication of PDAC with 60-80% of patients exhibiting symptoms at the time of cancer diagnosis. Targeting cachexia is needed to increase survival of PDAC patients. Tumor-derived pro-inflammatory cytokines can alter available metabolites such as iron and free fatty acids in multiple cancer types to drive tumor progression. We have shown that the pro-inflammatory cytokine lipocalin-2 (LCN2), an iron and fatty acid binding molecule, is overexpressed in PDAC and involved in signaling within the tumor microenvironment. Moreover, in a cancer-associated cardiomyopathy model, LCN2 interacts with iron-binding molecules, resulting in decreased free iron causing metabolic stress and cachexia. In the adipose tissue, LCN2 interacts with fatty acids to mediate changes in metabolism and thermogenesis. The mechanisms that drive cachexia in PDAC remain poorly understood, and no targeted therapies are available to control cachexia or its detrimental effects. Therefore, our long-term goals are to identify how PDAC contributes to the progression of cachexia by promoting changes in the adipose and skeletal muscle tissue metabolism and regeneration. We intend to leverage our findings to identify therapeutic targets that could mitigate cachexia symptoms and improve long-term survival in PDAC patients. We hypothesize that PDAC contributes to cachexia by secreting factors that: 1) alter iron and fatty acid levels to promote adipose and skeletal muscle tissue atrophy, and 2) alter skeletal muscle satellite cell differentiation, preventing muscle regeneration. To test our hypotheses we propose the following aims: 1) Determine changes in iron and fatty acid content that contribute to cachexia. We hypothesize that elevated LCN2 decreases free iron and alters free fatty acid content increasing metabolic stress in adipose and skeletal muscle tissue. Plasma, adipose, and skeletal muscle tissue from PDAC patients will be assessed for LCN2 expression, iron availability, and fatty acid content and correlated with clinical indicators of cachexia. Then, using genetically engineered mouse models (GEMMs) of PDAC (-/+ Lcn2), we will determine whether LCN2?s binding of fatty acids and iron drive adipose and skeletal muscle tissue wasting by assessing metabolism, oxidative stress, and autophagy. 2): Determine whether PDAC-secreted cytokines contribute to cachexia by altering differentiation of satellite cells. We hypothesize that increased expression of PDAC-secreted LCN2 promotes the dysregulation of satellite cells differentiation in the skeletal muscle by overstimulating the NF-KB/Pax7 signaling pathway. We will use satellite cells isolated from patients (+/- PDAC) and from mice with orthotopically implanted PDAC tumors +/- LCN2 expression to assess the impact of tumor-derived LCN2 on satellite cell differentiation and muscle regeneration.
Cachexia associated with pancreatic ductal adenocarcinoma (PDAC) is correlated with shorter survival, reduced efficacy of chemotherapy and surgery, and a reduction in quality of life. Our project will provide meaningful insights related to PDAC tumor-derived secreted factors that mediate adipose and skeletal muscle tissue metabolism that are part of the cachexia process. Results will provide important findings that could guide new therapeutic approaches to treating PDAC-associated cachexia and improving PDAC patient outcomes.
