Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice

• Published in: PloS one Vol. 12; no. 9; p. e0184455
• Main Authors: Chang, Hui-Hua, Moro, Aune, Takakura, Kazuki, Su, Hsin-Yuan, Mo, Allen, Nakanishi, Masako, Waldron, Richard T., French, Samuel W., Dawson, David W., Hines, O. Joe, Li, Gang, Go, Vay Liang W., Sinnett-Smith, James, Pandol, Stephen J., Lugea, Aurelia, Gukovskaya, Anna S., Duff, Michael O., Rosenberg, Daniel W., Rozengurt, Enrique, Eibl, Guido
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.09.2017; Public Library of Science (PLoS)
• Subjects: Amino Acid Substitution; Animal tissues; Animals; Autophagy; Autophagy - genetics; Biology and Life Sciences; Body Weight; Cancer; Cell death; Codon; Computational Biology - methods; Diet; Diet, High-Fat - adverse effects; Disease; Disease Models, Animal; Energy Intake; Epidemiology; Exome; Extracellular Matrix - metabolism; Female; Females; Fibrosis; Gene sequencing; Genetic variance; Genetic Variation; Health risks; High-Throughput Nucleotide Sequencing; Incidence; Inflammation - etiology; Inflammation - pathology; K-Ras protein; Lesions; Male; Males; Medical prognosis; Medicine; Medicine and Health Sciences; Mice; Mimicry; Mutation; Obesity; Oncology; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - etiology; Pancreatic Neoplasms - pathology; Pathology; Phagocytosis; Physicians; Proto-Oncogene Proteins p21(ras) - genetics; Surgery; Veterans; Los Angeles California; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0184455

Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.