The role of the macroenvironment in pancreatic cancer-induced cachexia

PROJECT SUMMARY: OVERALL The overall goal of this Program Project is to gain a better understanding of the underlying mechanisms that drive cachexia in cancer patients, especially patients with pancreatic ductal adenocarcinoma (PDAC) that exhibit one of the highest incidences of cachexia among all tumor types. Cancer patients who have lost > 5% of their pre-illness weight are considered cachectic. In comparison, 85% of PDAC patients lose an average of 14% body weight, and recent published data show that any loss of body weight > 10% in this population leads to poorer survival. Although some improvements have been made in PDAC to extend the 5-year survival rate, this is still among the lowest rate of all solid tumors. Thus, until therapeutics are found to effectively treat PDAC, understanding the causes of cachexia is vital to improving treatment responses, quality of life, and potentially overall survival. The main innovative concept in our Program Project is the belief that to effective treat PDAC-induced cachexia one must consider the macroenvironment of this syndrome, so as to treat the tumor and the wasting of peripheral tissues at the same time. The effectors we focus on in this Program Project are part of the NF-B/IL-6/STAT3 signaling axis. Our hypothesize is that the NF-B/IL-6/STAT3 signaling axis is a central regulator of the macroenvironment in PDAC-induced cachexia. This hypothesis will be tested in 3 Projects under the support of 4 Cores. Project 1 focuses on the IL-6/STAT3 portion of the NF- B/IL-6/STAT3 signaling axis. Specifically, studies will define the participation of IL-6 and the IL-6 receptor acting through STAT3 to mediate fat and muscle loss. Project 2 focuses on NF-B within the signaling axis, exploring two fresh concepts in how NF-B functions in muscle stem cells to promote local muscle inflammation and in PDAC progression by modulating the surveillance of innate and adaptive immune cells. Project 3 will explore the IL-6/STAT3 axis within stroma fibroblasts. Specifically, how STAT3 signaling in stromal mesenchymal cells in the tumor and peripheral tissues produces an immunosuppressive macroenvironment that favors PDAC progression and cancer cachexia. Core A (Administration) will provide administrative structure for the organization of the program. Core B (Human Biospecimens) will maintain a repository of tissues from PDAC patients with and without cachexia and support next generation sequencing analysis. Core C (Immunophenotyping) will provide expertise in scRNA-Seq and multispectral imaging of the tumor, skeletal muscle, and fat in PDAC-induced cachexia. Core D (Biostatistics) will provide biostatistical support. This Program contains multiple points of integration founded on collaborations between NCI designated Cancers Centers at the Medical University of South Carolina and Indiana University and their respective Cancer Cachexia Programs. The outcome obtained from these studies will advance our basic understanding of tumor-muscle/fat interactions within a PDAC macroenvironment that will likely apply to other cancer conditions where cachexia contributes to the morbidity and mortality of patients.