胰腺由内分泌部分和外分泌部分组成，其交错结构表明内分泌细胞和外分泌细胞之间存在潜在的相互作用。尽管胰腺导管腺癌（PDAC）的肿瘤微环境已得到很好的表征，但胰腺内分泌细胞在癌变过程中的作用还相对不足。我们通过单细胞转录组测序、空间转录组测序和多重免疫组化描述了PDAC中内分泌细胞的变化。此后，在原位移植小鼠、KC小鼠和KPC小鼠中探讨了胰腺癌发生与内分泌变化之间的相互作用。最后，我们通过胰岛分离、体外共培养和体内共注射，证明了胰腺内分泌和外分泌部分相互作用的机制。我们发现胰腺内分泌细胞表现出显着不同的转录组特征，并且与外分泌部分的相互作用增强在 PDAC 中。具体来说，在所有变化中，胰多肽阳性（PPY）细胞随着癌灶的进展而急剧增加，这可能源于α和β细胞的转分化。有趣的是，研究证明PDAC细胞能够诱导胰腺α细胞和β细胞转分化为GCG PPY和INS PPY双阳性细胞，从而以旁分泌依赖性方式进一步促进PDAC的癌变和发展，并形成一种相互促进的机制。我们的研究系统地绘制了 PDAC 中胰腺内分泌细胞的变化，并阐明了 PDAC 致癌过程中潜在的内分泌-外分泌相互作用机制。同时，我们首次定义和表征了癌症相关内分泌细胞（CAE），从而进一步拓宽了PDAC微环境的组成。版权所有©2024 AGA研究所。由爱思唯尔公司出版。保留所有权利。

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.We depicted the changes of endocrine cells in PDAC by single-cell transcriptome sequencing, spatial transcriptome sequencing and multiplex immunohistochemistry. After that, the interaction between pancreatic carcinogenesis and endocrine changes was explored in orthotopic transplantation mice, KC mice and KPC 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.We found that pancreatic endocrine cells displayed significantly different transcriptomic characteristics and increased interaction with exocrine part in PDAC. Specifically, among all the changes, pancreatic polypeptide positive (PPY+) cells showed a sharp increment accompanied with 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 GCG+PPY+ and INS+PPY+ double-positive cells, which further promoted carcinogenesis and development of PDAC in a paracrine-dependent manner and formed a reciprocal interaction.Our study systematically maps the alteration of pancreatic endocrine cells in PDAC and elucidates the potential endocrine-exocrine interaction mechanisms during PDAC carcinogenesis. Meanwhile, we first time define and characterize cancer-associated endocrine cells (CAEs), thereby further broadening the composition of PDAC microenvironment.Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.