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BACKGROUND & AIMS: 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. METHODS: 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, KrasLSL-G12DPdx1-Cre mice, and KrasLSL-G12Dp53LoxPPdx1-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. RESULTS: 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 ß cells. Interestingly, it was proved that PDAC cells were able to induce the transdifferentiation of pancreatic α cells and ß 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. CONCLUSIONS: 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.
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Objective: Pancreatic cancer is one of the most aggressive malignancies, a robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making. Methods: A list of bioinformatic analysis were applied in public dataset to construct an immune-related signature. Furthermore, the most pivotal gene in the signature was identified. The potential mechanism of the core gene function was revealed through GSEA, CIBERSORT, ESTIMATE, immunophenoscore (IPS) algorithm, single-cell analysis, and functional experiment. Results: An immune-related prognostic signature and associated nomogram were constructed and validated. Among the genes constituting the signature, interleukin 1 receptor type II (IL1R2) was identified as the gene occupying the most paramount position in the risk signature. Meanwhile, knockdown of IL1R2 significantly inhibited the proliferation, invasion, and migration ability of pancreatic cancer cells. Additionally, high IL1R2 expression was associated with reduced CD8+ T cell infiltration in pancreatic cancer microenvironment, which may be due to high programmed cell death-ligand-1 (PD-L1) expression in cancer cells. Finally, the IPS algorithm proved that patients with high IL1R2 expression possessed a higher tumor mutation burden and a higher probability of benefiting from immunotherapy. Conclusion: In conclusion, our study constructed an efficient immune-related prognostic signature and identified the key role of IL1R2 in the development of pancreatic cancer, as well as its potential to serve as a biomarker for immunotherapy efficacy prediction for pancreatic cancer.
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Obesity is a significant risk factor for various cancers, including pancreatic cancer (PC), but the underlying mechanisms are still unclear. In our study, pancreatic ductal epithelial cells were cultured using serum from human subjects with diverse metabolic statuses, revealing that serum from patients with obesity alters inflammatory cytokine signaling and ferroptosis, where a mutual enhancement between interleukin 34 (IL-34) expression and ferroptosis defense was observed in these cells. Notably, oncogenic KRASG12D amplified their interaction and this leads to the initiation of pancreatic ductal adenocarcinoma (PDAC) in diet-induced obese mice via macrophage-mediated immunosuppression. Single-cell RNA sequencing (scRNA-seq) of human samples showed that cytokine signaling, ferroptosis defense, and immunosuppression are correlated with the patients' body mass index (BMI) during PDAC progression. Our findings provide a mechanistic link between obesity, inflammation, ferroptosis defense, and pancreatic cancer, suggesting novel therapeutic targets for the prevention and treatment of obesity-associated PDAC.