Investigating Adipocyte Bioenergetics and Dysfunction in Pancreatic Cancer

Résumé fourni par la source

Pancreatic cancer is known for its incredibly poor survival rate of 13% and only 3% for metastatic disease. Pancreatic Ductal Adenocarcinoma (PDAC) is the most common form of pancreas cancer; late detection results in advanced-stage disease at diagnosis, low probability of surgical resection, and poor chemotherapeutic response. While no direct cause of PDAC has been identified, obesity is a significant risk factor for PDAC. In 2020, it was reported that obesity had increased by 12% between 1999-2018 in the United States. This correlates with the rise of obesity-related cancers, specifically correlating with PDAC, which is to become the second leading cause of cancer-related death by 2025. Clinically, reports show obese PDAC patients have a three-month decrease in overall survival when compared to lean PDAC patients. Multiple studies have implicated obese white adipose tissue (WAT) as a major driver of obesity-dependent tumor progression. Our lab has shown that a diet-induced obesity model will increase PDAC area, proliferation, and weight compared to standard chow diet-fed lean mice. Furthermore, we have demonstrated that human-obese WAT-conditioned media will induce a proliferative effect on human PDAC cells, and mouse-obese WAT recapitulates the same impact on mouse PDAC cells. Given this, we suggest that obese WAT can be a major driver in two related but independent mechanisms: 1) metabolites from obese WAT can fuel PDAC growth, and 2.) inflammatory mediators generated in the obese WAT support PDAC progression. Therefore, we hypothesize that preventing lipid release and reducing inflammation of the WAT will reduce obesity dependent PDAC growth. To this end, data from our lab suggests that the metabolic subtype of PDAC correlates with cancer-induced lipolysis of adipocytes and subsequent uptake of liberated lipids from white adipocytes that, in turn, support its metabolic demands. In support of this, we show that PDAC hinders mitochondrial function in adipocytes, but by blocking the MAPK pathway, adipocyte mitochondrial function can be restored; theoretically, these metabolites will be used to meet the metabolic demand of the mitochondria. We observed that PDAC will incorporate free fatty acids, but what remains to be investigated is PDACs' use of inflammatory mediators from obese adipose. A specialized adipose called thermogenic adipose typically displays anti-inflammatory signatures and is thought to be protective against obesity. Therefore, we sought to induce this unique adipose via cold exposure in DIO mice to determine if it would reduce or reverse the effect obese adipose has on cancer progression. Our analysis via µCT imaging and histology of cold-exposed obese mice validates a preferential increase in total thermogenic adipose and a decrease in obese WAT. Importantly, we demonstrate a loss of pro-inflammatory factors and decreased tumor growth in cold-exposed mice. In conclusion, we have delineated new implications for the molecular mechanisms governing adipose-PDAC crosstalk by developing models that manipulate adipocytes to combat obesity-dependent PDAC growth.

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