Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma
| Autor: | Richard F. Dunne, Daniel B. Burkhardt, Xiaojian Zhao, Rebecca L. Cardone, Cathy Garcia, Charles S. Fuchs, Joshua J. Wilhelm, Richard G. Kibbey, Arjun Bhutkar, Jaffarguriqbal Singh, Andressa Dias Costa, Brian M. Wolpin, Lauren Lawres, Albert C. Koong, Kimberly Judith Dorans, Smita Krishnaswamy, Daniel T. Chang, Rebecca Robbins, Jonathan A. Nowak, Vibe Nylander, Sara A. Väyrynen, Aram F. Hezel, Mandar Deepak Muzumdar, Anna L. Gloyn, Melena D. Bellin, Mark I. McCarthy, Ana Babic, Katherine Minjee Chung, Tyler Jacks |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
endocrine system diseases
Cell Inflammation Biology Gene mutation medicine.disease_cause General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Fibrosis Pancreatic cancer medicine 030304 developmental biology 0303 health sciences geography Tumor microenvironment geography.geographical_feature_category business.industry Pancreatic islets Leptin fungi Islet medicine.disease digestive system diseases medicine.anatomical_structure Cancer research medicine.symptom Beta cell Carcinogenesis business 030217 neurology & neurosurgery |
| Zdroj: | PMC |
| Popis: | SUMMARYObesity 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 islet beta cell expression of the peptide hormone cholecystokinin (CCK) in tumors as an adaptive response to obesity. Furthermore, beta cell CCK expression promotes oncogenicKras-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. |
| Databáze: | OpenAIRE |
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