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| Status |
Public on Aug 12, 2020 |
| Title |
Endocrine-exocrine signaling in obesity-driven pancreatic ductal adenocarcinoma |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Bulk and single cell molecular analyses of human and murine samples define microenvironmental consequences of obesity that promote tumor development rather than new driver gene mutations. We observe increased inflammation and fibrosis and also provide evidence for significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta islet cell expression of the peptide hormone cholecystokinin (CCK) in tumors as an adaptive response to obesity. Furthermore, islet CCK expression promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment – rather than systemic effects – and implicate endocrine-exocrine signaling beyond insulin in PDAC development. Furthermore, our demonstration that these obesity-associated adaptations are reversible supports the use of anti-obesity strategies to intercept PDAC early during progression.
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| Overall design |
Islets from pancreata from ob/ob and wild-type (WT) mice
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| Contributor(s) |
Chung KM, Singh J, Lawres L, Dorans KJ, Garcia C, Burkhardt DB, Robbins R, Bhutkar A, Cardone R, Zhao X, Babic A, Vayrynen SA, Costa AD, Nowak JA, Chang DT, Dunne RF, Hezel AF, Koong AC, Wilhelm JJ, Bellin MD, Nylander V, Gloyn AL, McCarthy MI, Kibbey RG, Krishnaswamy S, Wolpin BM, Jacks T, Fuchs CS, Muzumdar MD |
| Citation(s) |
32304665 |
| Submission date |
Sep 10, 2019 |
| Last update date |
Aug 12, 2020 |
| Contact name |
Daniel Burkhardt |
| E-mail(s) |
dburkhardt@cellarity.com
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| Organization name |
Cellarity
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| Street address |
101 South Street, 6th Floor
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| City |
Somerville |
| State/province |
MA |
| ZIP/Postal code |
02145 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA564842 |
| SRA |
SRP221287 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE137236_filtered_counts.normalized.csv.gz |
51.5 Mb |
(ftp)(http) |
CSV |
| GSE137236_metadata.csv.gz |
430.8 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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