Understanding the pancreatic cancer microenvironment and macroenvironment

Cancer cachexia, or progressive weight loss featuring immunodysmetabolism, causes ~1/3 of cancer deaths. Cachexia is especially devastating in pancreatic ductal adenocarcinoma (PDAC), afflicting 85% of PDAC patients, most of whom present with weight loss. There is no effective treatment for PDAC and 5-year survival is ~9%. Thus, until PDAC can be cured early in its course, we must manage cachexia, because preserving muscle mass and function will promote response to cancer treatment, improve quality of life, and increase survival. Our work takes us into and out of the tumor, studying the body’s response to tumor cells. We strive to understand the crosstalk among organ systems (including muscle, adipose, liver, bone) and the neo-organ of the pancreatic tumor.

Discovery and profiling of molecular markers and drivers of cachexia

Leveraging cell culture systems, mouse models, and human biospecimens, we have identified novel mediators of cachexia, including the Myostatin/Activin/ACVR2B/SMAD, IL6/IL6R/GP130/STAT3, and SHH/GLI pathways. We have also identified markers and potential mediators of cachexia using transcriptomic and proteomic approaches using human tumor, adipose, muscle, and blood specimens.

Understanding heterogeneity in cancer cachexia

Using diverse models and patient data and biospecimens, we are interrogating the biological heterogeneity in cancer cachexia as a clue to finding targetable mechanisms. Our work has identified sex-specific differences in pancreatic cancer in mouse models and in patient data, work that has been reproduced and extended by others. Similarly, we are interrogating molecular characteristics of tumors and hosts that modulate the cachexia phenotype. We have developed multiple new models of cancer cachexia, including ovarian cancer, cancer plus chemotherapy, and cancer in obesity and aging.

Tumor tissue crosstalk in the macroenvironment of pancreatic cancer cachexia

Veterans Administration Merit Award I01CX002046

The majority of patients with pancreatic cancer will experience progressive and profound loss of adipose tissue and skeletal muscle. This condition, known as cachexia, increases treatment toxicity, reduces function, and causes some 25-30% of cancer deaths. Feeding is insufficient to prevent weight loss in patients with pancreatic cancer because the tumor orchestrates changes in whole body metabolism and inflammation. Here we seek to use specimens from patients with pancreatic cancer to interrogate the cross-talk between tumor, adipose tissue, and skeletal muscle in order to validate pathways discovered using mouse models. Using a “mouse hospital” of mouse cohorts implanted in the pancreas with a number of patient-derived tumor lines and treatment with standard chemotherapy regimens, we will also test a novel anti-cachexia therapy. These studies will provide essential clinical correlative, mechanistic, and pre-clinical data for future clinical trials. View the project details for "Tumor tissue crosstalk in the macroenvironment of pancreatic cancer cachexia".

IL-6/STAT3/NF-kB in Adipose-Muscle Crosstalk in the Pancreatic Cancer Macroenvironment

Project 1 of NCI Award 5P01CA236778

The role of the macroenvironment in pancreatic cancer-induced cachexia, with collaborators at Medical University of South Carolina, Indiana University, and University of Copenhagen’s Herlev Gentofe Hospital in Denmark

Overall, our Program team hypothesizes that PDAC tumor progression and cachexia is highly orchestrated by an IL-6/IL6R/STAT3/NF-kB signaling axis. Project 2 will test NF-kB in muscle inflammation and tumor progression, and Project 3 will study IL-6/STAT3/NF-kB in tumor-stroma- immune interactions and the macroenvironment. Project 1 of this Program focuses on the crosstalk between adipose and skeletal muscle induced by PDAC tumors. We hypothesize that PDAC induces a feed-forward loop among tumor, fat, and muscle whereby tumor-induced IL-6 and other signals activate adipose STAT3 and lipolysis, products of which are taken up by muscle leading to myosteatosis, PKC-θ activation and subsequent myofiber STAT3, NF-kB and PDK4 activation, which promote dysmetabolism, local inflammation and production of soluble IL6R to feed-forward activate adipose wasting. Blocking this cycle will preserve adipose and muscle wasting in PDAC. Using genetic mouse models, human specimens, advanced single cell resolution sequencing as well as correlative cachexia studies in a clinical trial, we will test our hypothesis in these specific aims: AIM 1. Interrogate the mechanisms of adipose-to-muscle crosstalk in the macroenvironment of PDAC cachexia. AIM 2. Interrogate mechanisms of muscle-to-adipose crosstalk in the macroenvironment of PDAC cachexia. AIM 3. Interrogate manifestations and mechanisms of the IL-6/IL6R/STAT3/NF-kB pathway in patients with PDAC cachexia. View the project details for "IL-6/STAT3/NF-kB in Adipose-Muscle Crosstalk in the Pancreatic Cancer Macroenvironment".

The Musculoskeletal Cost of Organ Repair

NIGMS Award R01GM137656

Interrogating liver-muscle crosstalk in the context of liver growth and injury (with Leonidas Koniaris, MD).

Following surgery or traumatic injury, the body requires a large quantity of amino acids and fats to regenerate and heal damaged tissues and organs. This process, however, generally occurs during a time of impaired eating and works through a mechanism whereby the body massively catabolizes tissues including muscle and fat. Here we seek to understand the molecular and cellular processes involved in organ cross-talk after injury, focusing on the mediators IL-6, YAP and TAZ in the inter-organ communication of tissues, organs, and muscle in the context of severe injury. View the project details for "The Musculoskeletal Cost of Organ Repair".