Abstract 1603: Intra-pancreatic fat promotes the progression of PDAC by activating thermogenesis

Abstract Background: The presence of minimal intra-pancreatic fat deposition (IPFD) in the healthy human pancreas has been demonstrated in numerous studies. But excess IPFD, or fatty pancreas disease, leads to a wide array of diseases, including but not limited to diabetes, pancreatitis, and pancreatic ductal adenocarcinoma (PDAC). Remarkably, PDAC patients with excessive intra-pancreatic fat accumulation are commonly associated with a poor prognosis compared to those with minimal deposition. However, the interaction between tumor and intra-pancreatic adipose tissue remains elusive. Here, we evaluated the pancreatic fat infiltration in normal people and patients with PDAC respectively, and explored the mechanism of how intra-pancreatic fat affects the progression of PDAC. Methods: Magnetic resonance imaging (MRI) and clinical biopsy specimens were used to assess the degree of pancreatic fat infiltration in PDAC patients and healthy control individuals. The C57BL/6J mice injected orthotopically with KPC cells and adipocytes, high-fat diet (HFD)-induced obesity KC (Pdx1-Cre; KrasLSL-G12D/WT) mice, and KC; ob/ob mice were established to dynamically observe how adipocytes affect tumor progression in vivo. The snRNA-seq of tumor samples and proteomics of conditional medium of PDAC cell lines were performed to identify the mechanism of interaction between cancer cells and adipocytes. Results: We found that patients with PDAC presented excess intra-pancreatic fat deposition more frequently than healthy individuals, and the degree of fat infiltration was positively correlated with the tumor burden of PDAC patients. HFD-induced obesity KC mice and KC; ob/ob mice showed a higher degree of IPFD, which contributed to tumor growth and low survival rates of mice. Additionally, the expression of uncoupling protein 1 was upregulated in PDAC patients and KPC (Pdx1-Cre; KrasLSL-G12D/WT; p53LSL-R172H/WT) mice compared to normal controls. Constantly, the snRNA-seq of PDAC samples demonstrated the increase in thermogenic signature. In vitro, C3H10T1/2 cells treated with conditional medium from pancreatic cancer cell lines or co-cultured with pancreatic cancer cell lines showed increased expression of browning markers and elevated oxygen consumption rate. Specifically, combined analysis of the proteomic of T3M4 and CFPAC-1 conditional medium and the snRNA-seq revealed that pancreatic cancer cells secreted integrin β4 (ITGB4) to improve the thermogenesis of intra-pancreatic adipocytes (IPA), which in turn promoted cancer cell progression. Conclusion: Parts of PDAC patients present excess intra-pancreatic fat accumulation, a process associated with tumor growth and poor prognosis. Mechanistically, pancreatic cancer cells activate the thermogenesis of IPA by secreting ITGB4, and then the thermogenetic adipocytes fuel the progression of the tumor in response. Citation Format: Xinpeng Yin, Yuan Chen, Ruiyuan Xu, Chenglin Hu, Chengcheng Wang, Yupei Zhao. Intra-pancreatic fat promotes the progression of PDAC by activating thermogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1603.