1653P - The activated thermogenesis of intra-pancreatic fat fuels the progression of pancreatic cancer

Background

The presence of minimal intra-pancreatic fat deposition (IPFD) in the healthy human pancreas has been demonstrated in numerous studies. But excess IPFD, leads to a wide array of diseases, including but not limited to diabetes, pancreatitis, and pancreatic cancer (PC). Remarkably, PC patients with excessive intra-pancreatic fat accumulation are commonly associated with a poor prognosis compared to those with minimal IPFD. However, the interaction between tumor and IPFD remains elusive. Here, we evaluated the pancreatic fat infiltration in normal people and patients with PC respectively, and explored how intra-pancreatic fat accelerates tumor progression.

Methods

Magnetic resonance imaging (MRI) and clinical biopsy specimens were used to assess the degree of pancreatic fat infiltration in PC patients and healthy control individuals. The KC, KPC, KCO, and AAV8-ADIPOQ-DTA mice were established to demonstrate that IPFD promoted tumor progression. The single-nucleus sequencing of pancreatic fat tissue and proteomic of PC cell lines were performed to identify the mechanism of interaction between cancer cells and adipocytes.

Results

We found that patients with PC presented excess intra-pancreatic fat deposition more frequently than control individuals, and the degree of fat infiltration was positively correlated with the tumor size of PC patients. High-fat diet KPC mice or KCO mice showed a higher degree of IPFD, which contributed to tumor growth and low survival rates of mice. Besides, the expression of uncoupling protein 1 (UCP1) was upregulated in PC patients or spontaneous tumor mice compared to normal controls. Constantly, the single-nucleus sequencing of pancreatic fat tissue of PC patients demonstrated the increase in thermogenesis features. Specifically, we revealed that PC cells improved the thermogenesis of intra-pancreatic adipose tissue, which in turn promoted PC cell proliferation.

Conclusions

We demonstrated that excess intra-pancreatic fat infiltration fuels the progression of PC, and selectively eliminating fat in the pancreas inhibits tumor growth. Mechanistically, PC cells promote the browning of adipocytes, and then the activated adipocytes enhance the proliferation and migration of cancer cells in response.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

PUMCH.

Disclosure

All authors have declared no conflicts of interest.