Abstract 4323: Ancestral obesity and early life metabolic dysfunction accelerates acinar-to-ductal reprogramming and PanIN/PDAC development in the P48Cre/+ /KrasG120/+ mouse model

Abstract

Abstract Pancreatic cancer is virtually an incurable malignancy, with overall 5-year survival rates of about 7%. Excess body weight and metabolic dysfunction are believed to account for up to 50% of all pancreatic cancers. Epidemiological studies suggest that timing of obesity—and underlying metabolic dysfunction—onset is important in determining pancreatic cancer rates: Early and young adult abdominal obesity is more strongly associated with this cancer than obesity that develops later in life. However, the mechanisms behind this association are not understood. Children of obese parents are more likely to develop overweight, insulin resistance and diabetes. Here, we evaluated the effects of paternal overweight in the susceptibility of pancreatic cancer in offspring using the P48Cre/+ /KrasG120/+ mouse model of pancreatic cancer. LSL-KrasG120/+ and P48Cre/+ male mice were fed either an obesity-inducing (OID) or control (CO) diet for 8 weeks from weaning to sexual maturity. At the end of this period, OID- and CO-fed male mice were housed with female mice, with free access to CO diet, for 3 days. Pregnant dams were kept on the CO diet during pregnancy and after giving birth. Pups were weaned from mothers at 21 days of age, fed a standard chow diet for the extent of the study and weighed weekly. While both female and male OID offspring had higher weight at birth (p=0.005), only OID females were heavier at weaning (p=0.02) compared to CO. Those gender-specific differences were also observed in metabolic parameters with OID male, but not female, offspring showing impaired glucose tolerance (p<0.05) compared to CO. Interestingly, OID offspring also had significantly higher rates of acinar-to-ductal reprogramming as assessed by the ratio of CPA1,+Sox9+ pancreatic cells. Accordingly, we also observed accelerated development of high grade PanIN at 2 and 6-8 months of age in OID offspring compared to CO of the P48Cre/+ /KrasG120/+ genotype (p=0.02; p=0.007). Additionally, we found that the expression of Tenascin C (TNC), an ECM glycoprotein shown to suppress apoptosis, was upregulated in OID offspring (p=0.03). In line with that, OID offspring displayed increased (p=0.03) collagen content and decreased apoptosis (p=0.02) in pancreatic lesions compared to CO. In conclusion, an ancestral history of overweight through the paternal lineage and ensuing metabolic dysfunction in offspring increases their susceptibility to pancreatic cancer development. This increase was associated with higher acinar-to-ductal reprogramming and TNC expression, and reduced apoptosis in pancreatic lesions. While the exact mechanisms still need to be elucidated, our study offers some insights on why early obesity and metabolic dysfunction are more strongly associated to pancreatic cancer in humans. Citation Format: Raquel Santana, Johan Clarke, Ana Cristina Curi, Ali Baird, M Idalia Cruz, Bhaskar Kallakury, Sonia de Assis. Ancestral obesity and early life metabolic dysfunction accelerates acinar-to-ductal reprogramming and PanIN/PDAC development in the P48Cre/+ /KrasG120/+ mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4323.