PO.ET03.04 · 实验与分子治疗
SRSF1协调剪接导向的双引擎葡萄糖代谢，驱动糖尿病相关胰腺癌的化疗耐药
SRSF1 orchestrates splicing-directed dual-engine glucose metabolism driving chemoresistance in diabetes-associated pancreatic cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：合并2型糖尿病（T2DM）的胰腺导管腺癌（PDAC）患者表现出显著更差的治疗反应和更短的生存率。然而，糖尿病驱动的化疗耐药和免疫抑制背后的分子机制仍知之甚少。本研究旨在阐明糖尿病微环境如何通过剪接-代谢轴促进PDAC的化疗耐药。
方法：我们利用来自28例接受AG化疗的晚期PDAC患者的临床样本、T2DM相关PDAC小鼠模型（KPC、KPSC）、患者来源类器官以及多种体内模型，研究了SRSF1介导的剪接调控。机制研究包括scRNA-seq、eCLIP-seq、ATAC-seq、RIP、ChIP-qPCR和代谢流分析。
结果：本研究揭示，合并糖尿病的胰腺癌易发生化疗耐药，伴随SRSF1驱动的反向剪接比例升高和丙酮酸代谢改变。机制研究发现，糖尿病微环境中的乳酸积累诱导了SRSF1蛋白的K48乳酸化，增强了其稳定性并促进反向剪接事件。SRSF1调控PSMA3-AS1从线性剪接向反向剪接的转换，生成circ-PSMA3-AS1，最终促进代谢酶DLAT和LDHA的转录上调。DLAT/LDHA通过增强线粒体融合和糖酵解提供代谢韧性，使细胞能够同时激活TCA循环和糖酵解产能系统以获得化疗耐药。此外，这种代谢重塑通过上调PD-L1和持续产生乳酸深刻影响肿瘤免疫微环境，导致免疫逃逸、抑制CD8+ T细胞功能并促进Treg扩增。这一过程构成了一个自我强化的正反馈环路，导致糖尿病相关胰腺癌的难治性。基于这些机制发现，我们开发了一种三联组合疗法（小檗碱 + 抗PD1 + AG），靶向SRSF1、DLAT和LDHA，同时降低葡萄糖和肿瘤乳酸水平，在糖尿病PDAC模型中显著提高了治疗疗效。
结论：本研究揭示了糖尿病相关PDAC不良预后背后的机制框架，并提供了一种可临床转化的治疗策略。剪接-代谢-免疫轴的发现为靶向癌症治疗中的代谢脆弱性开辟了新途径，对日益增长的糖尿病癌症患者群体具有特别重要的意义。
查看英文原文 English abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) patients with concurrent type 2 diabetes mellitus (T2DM) exhibit significantly worse treatment responses and shorter survival rates. However, the molecular mechanisms underlying diabetes-driven chemoresistance and immune suppression remain poorly understood. This study aims to elucidate how the diabetic microenvironment promotes PDAC chemoresistance through the splicing-metabolism axis.
Methods: We investigated SRSF1-mediated splicing regulation using clinical samples from 28 advanced PDAC patients receiving AG chemotherapy, T2DM-associated PDAC mouse models (KPC, KPSC), patient-derived organoids, and multiple in vivo models. Mechanistic studies included scRNA-seq, eCLIP-seq, ATAC-seq, RIP, ChIP-qPCR, and metabolic flux analysis.
Results: This study revealed that pancreatic cancer with concurrent diabetes is prone to chemoresistance, accompanied by SRSF1-driven elevated back-splicing ratios and altered pyruvate metabolism. Mechanistic investigation found that lactate accumulation in the diabetic microenvironment induced K48 lactylation of SRSF1 protein, enhancing its stability and promoting back-splicing events. SRSF1 regulated the linear-to-back splicing conversion of PSMA3-AS1 to circ-PSMA3-AS1, ultimately promoting transcriptional upregulation of metabolic enzymes DLAT and LDHA. DLAT/LDHA provided metabolic resilience through enhanced mitochondrial fusion and glycolysis, enabling cells to activate both TCA cycle and glycolytic energy-producing systems to acquire chemoresistance. Additionally, this metabolic remodeling profoundly impacted the tumor immune microenvironment through upregulated PD-L1 and sustained lactate production, causing immune evasion, suppressing CD8+ T cell function, and promoting Treg expansion. This process constituted a self-reinforcing positive feedback loop, resulting in the intractability of diabetes-associated pancreatic cancer. Based on these mechanistic discoveries, we developed a triple combination therapy (Berberine + anti-PD1 + AG) targeting SRSF1, DLAT, and LDHA while reducing glucose and tumor lactate levels, significantly improving treatment efficacy in diabetic PDAC models.
Conclusions: This study reveals the mechanistic framework underlying poor outcomes in diabetes-associated PDAC and provides a clinically translatable therapeutic strategy. The discovery of the splicing-metabolism-immunity axis opens new avenues for targeting metabolic vulnerabilities in cancer treatment, with particular significance for the growing population of diabetic cancer patients.
利益披露 Disclosure
Z. Wang, None..
Y. Chen, None..
J. Lu, None..
S. Zhu, None..
H. Lin, None..
Y. Chen, None..
H. Zhang, None..
S. Chen, None.