The Peptide Hormone Cholecystokinin Links Obesity To

Published OnlineFirst May 1, 2020; DOI: 10.1158/2159-8290.CD-RW2020-065

RESEARCh wATCh

Pancreatic Cancer

Major Finding: Beta-cell cholecystokinin Concept: Early weight loss in this Impact: This study mechanistically expression in obese mice promoted pan- mouse model suppressed tumorigene- links obesity to PDAC and suggests creatic ductal adenocarcinoma (PDAC) . sis, but later-stage weight loss did not . when intervention may be effective . the PePtide horMone choLecYstoKinin LinKs obesitY to PAncreAtic cAncer Obesity is a contributor to pancreatic ductal ade- tions in the fi broinfl ammatory microenvironment nocarcinoma (PDAC), but the mechanisms under- were not causative in PDAC development could not lying this phenomenon are not fully established. be ruled out. Interestingly, although pancreatic islets Furthermore, it is unclear whether or at what point showed evidence of obesity-induced adaptation, during PDAC development weight-loss interven- increased insulin levels or insulin signaling did not tions may be benefi cial. To investigate this, Chung, appear to be to blame for the increase in tumorigen- Singh, Lawres, Dorans, and colleagues developed esis in obese mice. Instead, upregulation of the pep- an autochthonous mouse model of Kras-mutant, tide hormone cholecystokinin (CCK) by beta cells genetically obesity-driven PDAC. These mice exhibited early- in obese mice was observed to promote PDAC development, onset ob esity due to leptin defi ciency and had more rapid PDAC and increased obesity in humans without known malignancy progression and shortened survival compared with nonobese positively correlated with CCK expression. The increased CCK mice. Leptin restoration reduced obesity and stunted tumor expression seen with obesity in mice appeared to be related to growth to a degree proportional to the amount of weight lost, beta-cell proliferation and transcription-factor expression, and but only when weight loss occurred at an early stage of tumo- increased CCK expression’s synergy with Kras mutation seemed rigenesis—restoration of leptin after development of advanced to rely on acinar-cell proliferation and ductal transformation. tumors, despite inducing weight loss, did not improve sur- In summary, this work provides mechanistic insight into the vival. Obesity-driven PDAC development was not dependent contribution of obesity to PDAC development and highlights on accumulation of additional driver mutations beyond the the potential for weight loss or related pharmacologic interven- preexisting activating Kras mutation. Tumors from obese mice tion to reverse obesity’s effects in early-stage disease. n exhibited microenvironment changes characterized by mark- edly increased infl ammation and fi brosis, but the anti-infl am- Chung KM, Singh J, Lawres L, Dorans KJ, Garcia C, Burkhardt DB, matory drug aspirin and the antifi brotic drug metformin did et al. Endocrine-exocrine signaling drives obesity-associated pancreatic not affect disease progression; thus, the possibility that altera- ductal adenocarcinoma. Cell 2020 Apr 17 [Epub ahead of print].

Mutations

Major Finding: Many oncogenes contain Concept: Cancer cells with multiply Impact: This work reveals the frequency multiple individually weak mutations mutated PIK3CA were dependent on and impact of multiple driver mutations that collectively promote oncogenesis . PIK3CA and sensitive to PI3K inhibitors . in oncogenes across cancers . oncogenes hit bY MuLtiPLe cooPerAting MutAtions Are coMMon in cAncers Although there have been some reports of multiple driver analysis revealed six multiple mutation–positive oncogenes mutations affecting the same oncogene, systematic searches specifi c to certain cancer types; for example, multiple muta- for and detailed characterizatio n of such alterations has been tions in NOTCH1 were prevalent in T-cell acute lymphoblastic lacking. In an analysis of 60,954 samples representing all types leukemia. In vitro experiments and in vivo xenotransplantation of cancer, Saito, Koya, and colleagues found that the presence experiments demonstrated that, whereas each individual muta- of multiple mutations was common in oncogenes, especially tion in multiply mutated oncogenes may have been of little mutant variants of PIK3CA and EGFR, each of which was consequence, their combined effects were much more strongly affected by multiple mutations in 10% of cases. The proportion oncogenic. Interestingly, cancer cell lines with PIK3CA multiple of synonymous mutations in oncogenes with multiple muta- mutations were more dependent on PIK3CA and its partner tions was low, including in oncogenes in which both mutations AKT1 and were more susceptible to PI3K inhibitors than lines appeared to be under positive selection equivalent to the posi- without multiple mutations in PIK3CA. In summary, this work tive selection observed for single mutations, implying that the shows that the presence of multiple mutations in the same mutations in these oncogenes are driver–driver pairs. In most oncogene is relatively common, and these mutations act in cases, multiple mutations in oncogenes were observed in cis, concert to promote oncogenesis even in the absence of strong and a unique mutational pattern (as defi ned by mutation type, individual effects. n position, and amino acid–residue substitution) was observed in oncogenes bearing multiple mutations. Collectively, the Saito Y, Koya J, Araki M, Kogure Y, Shingaki S, Tabata M, et al. observed mutational patterns implied that mutational selection Landscape and function of multiple mutations within individual in these oncogenes was mediated by cis-acting effects. Deeper oncogenes. Nature 2020 Apr 8 [Epub ahead of print].

June 2020 CANCER DISCOVERY | 759

The Peptide Hormone Cholecystokinin Links Obesity to Pancreatic Cancer

Cancer Discov 2020;10:759. Published OnlineFirst May 1, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2020-065

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