Tumor-Associated Schwann Cell Remodeling under Metabolic Stress via Lactate Sensing Orchestrates

Diabetes mellitus (DM) is a known risk factor for pancreatic cancer, but the underlying mechanisms remain elusive. Using in vivo models of diabetes-driven pancreatic tumorigenesis and metabolomics analysis, we demonstrate that metabolic stress induced by DM promotes pancreatic cancer progression by remodeling tumor-associated Schwann cells (TASs), impairing CD8+ T cell function. We discover that Mettl16+ Cd276+ Nectin2+ Schwann cells play a crucial role in mediating the pro-carcinogenic effects of lactate. Remodeled METTL16+ Schwann cells secret immune evasion factors (CD276, NECTIN2), contributing to anti-PD1 resistance. Furthermore, rosuvastatin was identified in this study as a novel METTL16 inhibitor for pancreatic cancer under metabolic stress. In conclusion, our study underscores the critical role of lactate in the metabolic reprogramming of pancreatic cancer mediated by Schwann cell remodeling, revealing novel pathways for therapeutic intervention.

糖尿病（Diabetes mellitus, DM）是公认的胰腺癌风险因素，但其潜在致病机制仍有待阐明。本研究借助糖尿病驱动胰腺肿瘤发生的体内模型与代谢组学分析，证实糖尿病诱导的代谢应激可通过重塑肿瘤相关施万细胞（tumor-associated Schwann cells, TASs）、损伤CD8阳性T细胞（CD8+ T cell）功能，进而促进胰腺癌进展。研究发现，Mettl16阳性、Cd276阳性、Nectin2阳性施万细胞在介导乳酸的促癌效应中发挥关键调控作用。经代谢重塑的METTL16阳性施万细胞会分泌免疫逃逸因子CD276与NECTIN2，进而介导抗PD-1治疗耐药。此外，本研究还鉴定出瑞舒伐他汀可作为代谢应激状态下胰腺癌治疗的新型METTL16抑制剂。综上，本研究明确了乳酸在施万细胞重塑介导的胰腺癌代谢重编程中的核心作用，揭示了全新的治疗干预通路。

搜集汇总

背景与挑战

背景概述

该数据集研究了糖尿病背景下乳酸感知通过重塑肿瘤相关雪旺细胞促进胰腺癌进展的机制，揭示了METTL16+雪旺细胞的关键作用和rosuvastatin作为潜在治疗药物的可能性。数据集包含代谢组和单细胞RNA测序数据，为胰腺癌代谢重编程研究提供了重要资源。