1647P - Cancer-associated endocrine cell: A novel component of tumor microenvironment in pancreatic cancer

Background

Pancreatic cancer is a highly fatal and aggressive disease due to its discouraging mortality and clinical treatment efficacy. Pancreas is composed of endocrine and exocrine parts, and the interlacing structure of them reminds us of the potential interaction between endocrine and exocrine cells in the oncogenesis and development of pancreatic cancer.

Methods

We depicted the changes of pancreatic endocrine cells in pancreatic cancer tissues by single-cell transcriptome sequencing, spatial transcriptome sequencing and multiplexed immunohistochemistry in human as well as in mouse models. After that, the interaction and sequence between pancreatic cancer oncogenesis and endocrine changes was explored in orthotopic transplantation 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.

Results

We found that, compared with normal pancreatic tissue, pancreatic endocrine cells displayed significantly different transcriptomic characteristics and increased interaction with exocrine part in pancreatic cancer tissues. Specifically, pancreatic polypeptide positive (PP+) cells showed a sharp increment accompanied with the progression of the cancer lesion. From an evolutionary perspective, the increased PP+ cells might be derived from the trans differentiation of α and β cells. Interestingly, in vivo and in vitro experiments proved that pancreatic cancer cells were able to induce the trans differentiation of α cells and β cells into GCG+PP+ and INS+PP+ double-positive cells, which further promoted pancreatic cancer proliferation in a paracrine-dependent manner and formed a positive feedback loop.

Conclusions

Our study systematically mapped the changes of pancreatic endocrine cells in pancreatic cancer and elucidated their relationship with pancreatic cancer oncogenesis and development. Meanwhile, we first time defined and characterized cancer-associated endocrine cells (CAE), which indicated that pancreatic endocrine cells should be an important component of pancreatic cancer microenvironment, thereby providing novel ideas for early diagnosis and targeted therapy of pancreatic cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Nature Science Foundation of China, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, China Postdoctoral Science Foundation.

Disclosure

All authors have declared no conflicts of interest.