Effect of tumor microenvironment in pancreatic cancer on the loss of β-cell mass: implications for type 3c diabetes

Background: To explore the complex interactions between the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) and the loss of β-cell mass, further elucidating the mechanisms of type 3c diabetes mellitus (T3cDM) onset.

Methods: Single-cell RNA sequencing was employed to analyze the PDAC TME, identifying cell interactions and gene expression changes of endocrine cells. Pathological changes and paraneoplastic islets were assessed in the proximal paratumor (PP) and distal paratumor (DP). Fractional β-cell area and islet density were compared among normal pancreas from donors and paraneoplastic tissues from non-diabetes mellitus (NDM) and T3cDM patients. TUNEL staining, RT-qPCR and CCK8 assay were applied to demonstrate the β-cell apoptosis.

Results: Tumor cells, immune cells and fibroblasts could interact with endocrine cells, and apoptotic pathways were activated in endocrine cells of the PP. The PDAC TME was characterized by marked inflammation, sever fibrosis and atrophy. The islets in the PP had lower fractional β-cell area (0.68 ± 0.65% vs. 0.86 ± 1.02%, P = 0.037) and islet density (0.54 ± 0.42 counts/mm² vs. 0.83 ± 0.90 counts/mm², P = 0.001) compared to those in the DP. The PDAC TME in T3cDM exerted a more significant impact on the paraneoplastic islets compared to NDM. Moreover, β-cell apoptosis was markedly increased in the PP compared to the DP in PDAC patients without diabetes, particularly in smaller islets. Apoptosis-related genes were highly expressed in INS-1E cells exposed to PANC-1 medium.

Conclusion: Our research revealed that the PDAC TME is usually accompanied by some pathological changes, including inflammation, fibrosis, and atrophy. These pathological changes are related to a reduction in β-cell mass and trigger the development of T3cDM.