Beta Cell Hormone CCK Drives Obesity-Linked Pancreatic Cancer
Publication Title: Beta cell-derived cholecystokinin drives obesity-associated pancreatic adenocarcinoma development
Summary
- Question
- This study investigated how the hormone cholecystokinin (CCK), produced by pancreatic beta cells (cells in the pancreas responsible for insulin secretion), contributes to the development of pancreatic adenocarcinoma (PDAC), a type of pancreatic cancer linked to obesity. The researchers aimed to determine whether beta cell-derived CCK drives tumor growth independently of insulin and how obesity-induced stress in beta cells promotes CCK expression.
- Why it Matters
- Pancreatic cancer, specifically PDAC, is a highly lethal disease with poor survival rates. Obesity is a known risk factor for PDAC, but the mechanisms linking obesity and cancer development remain unclear. Understanding the role of beta cell-derived CCK in this process is significant because it could uncover new therapeutic targets to prevent or treat obesity-associated pancreatic cancer. This research highlights the broader importance of endocrine (hormone-producing) and exocrine (enzyme-producing) pancreatic interactions in disease progression.
- Methods
- The researchers used genetically engineered mouse models of obesity and pancreatic cancer to study the role of beta cell-derived CCK. They analyzed gene expression in beta cells using single-cell RNA sequencing, a technique that measures gene activity at the level of individual cells. They also employed computational tools to trace the development of CCK-expressing beta cells and validate findings through experimental lineage tracing and molecular analysis.
- Key Findings
- The study revealed that obesity induces stress in beta cells, leading to the production of CCK through activation of specific cellular stress pathways. Beta cell-derived CCK was shown to drive pancreatic tumor development independently of insulin. Obese mice lacking CCK in their beta cells exhibited significantly reduced tumor growth. Additionally, CCK secretion altered the nearby exocrine cells in the pancreas, creating a tumor-permissive environment. This relationship between beta cell stress and cancer development was consistent across multiple models.
- Implications
- These findings identify beta cell-derived CCK as a critical driver of obesity-associated pancreatic cancer, shifting focus from insulin to CCK as a target for intervention. Therapeutically blocking CCK or its signaling pathways could reduce the risk of pancreatic cancer in obese individuals without disrupting normal insulin function or glucose regulation. The study also underscores the importance of addressing obesity-related metabolic stress to prevent cancer.
- Next Steps
- Future research should explore how CCK promotes tumor growth at the molecular level and whether similar mechanisms occur in humans. Clinical studies could evaluate the potential of CCK inhibitors as preventive or therapeutic treatments for obesity-associated pancreatic cancer. Additionally, investigating how other obesity-induced stress factors influence cancer progression could uncover further therapeutic opportunities.
- Funding Information
This research was supported by the National Institutes of Health (NIH) through the Yale Cancer Biology Institute and Yale Cancer Center and Smilow Cancer Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Full Citation
Garcia CC, Venkat A, McQuaid DC, Agabiti SS, Tong A, Mathew B, Cardone RL, Starble R, Ruiz CF, Zheng C, Sogunro A, Jacox JB, Loh KH, Kibbey RG, Krishnaswamy S, Muzumdar MD. Beta cell-derived cholecystokinin drives obesity-associated pancreatic adenocarcinoma development. Nature Communications 2026 DOI: 10.1038/s41467-026-69821-2.
Authors
Cathy Garcia
First AuthorDaniel McQuaid
First AuthorMD/PhD Student
Mandar Deepak Muzumdar, MD
Last AuthorAssociate Professor of Genetics and of Internal Medicine (Medical Oncology).
Smita Krishnaswamy, PhD
Last AuthorAssociate Professor of Genetics and of Computer Science