Abstract LB316: Endocrine pancreas alteration in pancreatic ductal adenocarcinoma

Abstract Background: The pancreas is central to energy homeostasis, playing essential roles in digestion and regulation of blood glucose. Exocrine pancreas contains large amounts of of hydrolytic enzyme which is responsible for the digestion. Acinar cells, as well as ductal cells, represent the prime components of exocrine pancreas. They are both supposed to be the origin of pancreatic ductal adenocarcinoma (PDAC) and the researches focused on these exocrine cells, as well as other components in pancreatic cancer, are numerous. Islet cells are crucial for glucose homeostasis and their identity are proved to be altered significantly during diabetes by single-cell RNA-sequencing (scRNA-seq). However, the presence or extent of variation of islet cells in PDAC is not established yet. Moreover, due to the low proportion of endocrine cells in pancreas, it is hard to analyze the data of endocrine cells by using published scRNA-seq data of PDAC. As a consequence of this underrepresentation, the function of endocrine cells in PDAC remains unclear. Methods: We used scRNA-seq, multiplex immunohistochemistry (mIHC), high-throughput spatial transcriptomic sequencing (Stereo-seq) to detect the alteration of endocrine pancreas in PDAC of human and mouse model. KPC mice (KrasLSL-G12Dp53LoxPPdx1-CreER) and pancreatic orthotopic transplantation mice were applied to verify the islet cell alteration in multiple stages of PDAC. We also performed islet isolation and purification to enhance the proportion of endocrine cells when preparing single-cell suspension. Cell co-culture experiments were used to determine the interaction between exocrine-endocrine compartments. Results: Through mIHC of islet cells in PDAC tissues and normal pancreas tissues of mice (KPC vs. C57BL/6J) as well as human (PDAC patients vs. healthy donors), we found the decreased proportions of inulin positive (INS+) cells and increased proportions of glucagon positive (GCG+) cells in PDAC tissues. Furthermore, the proportion of pancreatic polypeptide positive (PPY+) cells was significantly elevated in PDAC tissue in both human and murine. Then, we quantified the double-positive cells and found the proportions of INS+GCG+, INS+PPY+ and GCG+PPY+ were markedly increased in PDAC tissue. Additionally, through the experiments in mouse model, we found the islet cells altered gradually within the multiple stage of PDAC (normal-PanIN-PDAC). Finally, it was found that PDAC cells could induce the transdifferentiation of pancreatic α and β cells into GCG+PPY+ and INS+PPY+ double-positive cells, which further promoted PDAC proliferation in a paracrine-dependent manner and formed a reciprocal interaction. Conclusions: Our study systematically maps the alteration of pancreatic endocrine cells in PDAC and elucidates the potential interaction mechanisms between endocrine and exocrine cells during PDAC carcinogenesis. Meanwhile, it is suggested that pancreatic endocrine cells should be considered as an important component of the PDAC microenvironment. Citation Format: Yuan Chen, Xinpeng Yin, Ruiyuan Xu, Rexiati Ruze, Jianlu Song, Chenglin Hu, Chengcheng Wang, Yupei Zhao. Endocrine pancreas alteration in pancreatic ductal adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB316.