Abstract
Beta-cell cholecystokinin expression in obese mice promoted pancreatic ductal adenocarcinoma (PDAC).
Major Finding: Beta-cell cholecystokinin expression in obese mice promoted pancreatic ductal adenocarcinoma (PDAC).
Concept: Early weight loss in this mouse model suppressed tumorigenesis, but later-stage weight loss did not.
Impact: This study mechanistically links obesity to PDAC and suggests when intervention may be effective.
Obesity is a contributor to pancreatic ductal adenocarcinoma (PDAC), but the mechanisms underlying this phenomenon are not fully established. Furthermore, it is unclear whether or at what point during PDAC development weight-loss interventions may be beneficial. To investigate this, Chung, Singh, Lawres, Dorans, and colleagues developed an autochthonous mouse model of Kras-mutant, genetically obesity-driven PDAC. These mice exhibited early-onset obesity due to leptin deficiency and had more rapid PDAC progression and shortened survival compared with nonobese mice. Leptin restoration reduced obesity and stunted tumor growth to a degree proportional to the amount of weight lost, but only when weight loss occurred at an early stage of tumorigenesis—restoration of leptin after development of advanced tumors, despite inducing weight loss, did not improve survival. Obesity-driven PDAC development was not dependent on accumulation of additional driver mutations beyond the preexisting activating Kras mutation. Tumors from obese mice exhibited microenvironment changes characterized by markedly increased inflammation and fibrosis, but the anti-inflammatory drug aspirin and the antifibrotic drug metformin did not affect disease progression; thus, the possibility that alterations in the fibroinflammatory microenvironment were not causative in PDAC development could not be ruled out. Interestingly, although pancreatic islets showed evidence of obesity-induced adaptation, increased insulin levels or insulin signaling did not appear to be to blame for the increase in tumorigenesis in obese mice. Instead, upregulation of the peptide hormone cholecystokinin (CCK) by beta cells in obese mice was observed to promote PDAC development, and increased obesity in humans without known malignancy positively correlated with CCK expression. The increased CCK expression seen with obesity in mice appeared to be related to beta-cell proliferation and transcription-factor expression, and increased CCK expression's synergy with Kras mutation seemed to rely on acinar-cell proliferation and ductal transformation. In summary, this work provides mechanistic insight into the contribution of obesity to PDAC development and highlights the potential for weight loss or related pharmacologic intervention to reverse obesity's effects in early-stage disease.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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