Single-cell sequencing reveals the heterogeneity of pancreatic neuroendocrine tumors under the pattern of genomic instability and histological grading

Histological grading is the key factors affecting the prognosis of patients and instructive in guiding treatment and assessing recurrence in non-functional pancreatic neuroendocrine tumor (NF-Pan-NET). Approximately one-third of patients without copy number variation (CNV) alteration and the prognosis of these patients are better than that of patients with CNV alteration. Tumor classification based on CNV also showed significant value in evaluating prognosis. However, the difference between CNV and histological grading is unclear. Here, at single cell level, we analyzed the heterogeneity of tumor cells according to two classification criteria, genomic instability (including CNV alteration and tumor mutation burden) and histological grading. We found that the classification basis on genomic instability of the bulk tissues was better than histological grading in distinguishing tumor cells at scRNA-seq. We revealed that the activated core pathways of tumor cells were significantly different under different histological gradings and genomic instability patterns. In particular, patients with liver metastases had specific activation pathways. Deciphering the differences of the tumor microenvironment through single-cell sequencing, we found that tip cells, lymphatic endothelial cells, macrophages, CD1A+ dendritic cell, Treg, MAIT, ILC and CAFs might patriciate in the process of hepatic metastases, which will facilitate the understanding of the patterns to decode the malignant potential and of NF-Pan-NET. Single-cell RNA-seq profiling for primary pancreatic neuroendocrine tumor tissuess, adjacent pancreas and pancreatic neuroendocrine tumor from 17 patients with pancreatic neuroendocrine tumor: 3 cases of adjacent pancreas, 2 cases of liver metastases, 15 cases of primary tumors.