1. Cancer-Associated Endocrine Cells Participate in Pancreatic Carcinogenesis.
- Author
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Chen, Yuan, Yin, Xinpeng, Xu, Ruiyuan, Ruze, Rexiati, Song, Jianlu, Yin, Chenxue, Hu, Chenglin, Wang, Chengcheng, Xu, Qiang, and Zhao, Yupei
- Abstract
The pancreas is composed of endocrine and exocrine parts, and its interlacing structure indicates potential interaction between endocrine and exocrine cells. Although the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) has been well characterized, the role of pancreatic endocrine cells during carcinogenesis is relatively understudied. The changes of endocrine cells in PDAC by single-cell transcriptome sequencing, spatial transcriptome sequencing, and multiplex immunohistochemistry were depicted. After that, the interaction between pancreatic carcinogenesis and endocrine changes was explored in orthotopic transplantation mice, Kras
LSL-G12D Pdx1-Cre mice, and KrasLSL-G12D p53LoxP Pdx1-CreER mice. Finally, we proved the mechanism of the interaction between endocrine and exocrine parts of the pancreas through islet isolation, co-culture in vitro and co-injection in vivo. Pancreatic endocrine cells displayed significantly different transcriptomic characteristics and increased interaction with exocrine part in PDAC. Specifically, among all of the changes, pancreatic polypeptide–positive cells showed a sharp increment accompanied by the progression of the cancer lesion, which might be derived from the transdifferentiation of α and β cells. Interestingly, it was proved that PDAC cells were able to induce the transdifferentiation of pancreatic α cells and β cells into glucagon-pancreatic polypeptide and insulin-pancreatic polypeptide double-positive cells, which further promoted carcinogenesis and development of PDAC in a paracrine-dependent manner and formed a reciprocal interaction. This study systematically maps the alteration of pancreatic endocrine cells in PDAC and elucidates the potential endocrine–exocrine interaction mechanisms during PDAC carcinogenesis. In addition, cancer-associated endocrine cells are defined and characterized, thereby further broadening the composition of PDAC microenvironment. [Display omitted] Pancreatic endocrine cells are systematically altered in pancreatic ductal adenocarcinoma, defined as cancer-associated endocrine cells, in which pancreatic polypeptide–positive cells form reciprocal interactions with exocrine cells to promote pancreatic carcinogenesis. [ABSTRACT FROM AUTHOR]- Published
- 2024
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