胰腺癌中基质刚度调节的IGF2BP2通过鞘磷脂代谢驱动免疫逃避

IF 25.7 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Gastroenterology Pub Date : 2025-03-28 DOI:10.1053/j.gastro.2025.03.019

Rong Tang, Zifeng Zhang, Xiaomeng Liu, Yingna Liao, , Mingming Xiao, Yangyi Li, Cong Zhou, Zhen Tan, Chaoyi Zhang, Chen Chen, Zeyin Rong, Yuan Liu, Pengcheng Li, Qiong Du, Qing He, Yubin Lei, Zijian Wu, Siyuan Lu, Jin Xu, Xianjun Yu

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引用次数: 0

摘要

背景,免疫疗法在癌症治疗中显示出令人鼓舞的效果；然而，它对胰腺导管腺癌（PDAC）仍然基本无效。n6 -甲基腺苷（m6A）在癌症生物学中起着至关重要的作用，但在免疫逃避方面尚未完全了解。本研究旨在阐明m6A修饰与PDAC免疫逃避的关联和机制，并提出临床干预策略。方法对122例PDAC患者进行多模式队列研究，整合转录组学分析、成像质细胞术和m6A定量，以鉴定与免疫抑制性肿瘤微环境（TME）和临床结果相关的m6A调节因子。研究结果在六个独立的PDAC队列中得到验证。MeRIP、RIP和RNA pull-down等检测证实IGF2BP2与靶标结合，而scRNA-seq、流式细胞术和mIHC分析了TME。临床前干预在PDAC类器官、患者来源的组织片段和人源化小鼠模型中进行了测试。结果我们的综合分析发现m6A解读蛋白IGF2BP2是PDAC预后不良的关键因素，与效应细胞浸润减少和纤维化TME有关。PDAC的高基质刚度稳定了IGF2BP2，随后通过上调SGMS2促进鞘磷脂合成。这一途径促进了PD-L1在膜脂筏上的定位，增强了免疫逃逸。PDAC的弹性特性使IGF2BP2/SGMS2过表达患者的无创筛查成为可能。破坏鞘磷脂合成可以提高人源化小鼠的抗肿瘤免疫能力，抑制PDAC的生长，突出了PDAC的免疫治疗机会。这些发现强调了外源性基质刚度与igf2bp2调节的鞘磷脂合成之间的重要相互作用，为PDAC的免疫治疗策略确定了一个有希望的靶点。

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Stromal Stiffness-Regulated IGF2BP2 in Pancreatic Cancer Drives Immune Evasion via Sphingomyelin Metabolism

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Stromal Stiffness-Regulated IGF2BP2 in Pancreatic Cancer Drives Immune Evasion via Sphingomyelin Metabolism

Background & aims

Immunotherapy has shown promising results in cancer treatment; however, it remains largely ineffective for pancreatic ductal adenocarcinoma (PDAC). N6-methyladenosine (m6A), known for its crucial role in cancer biology, is not yet fully understood regarding immune evasion. This study aims to elucidate the associations and mechanisms linking m6A modification with immune evasion in PDAC and propose strategies for clinical intervention.

Methods

A multimodal PDAC cohort of 122 patients was developed, integrating transcriptomic profiling, imaging mass cytometry, and m6A quantification to identify m6A regulators associated with immunosuppressive tumor microenvironment (TME) and clinical outcomes. Findings were validated across six independent PDAC cohorts. Assays including MeRIP, RIP, and RNA pull-down confirmed that IGF2BP2 binds to targets, while scRNA-seq, flow cytometry, and mIHC profiled the TME. Preclinical interventions were tested in PDAC organoids, patient-derived tissue fragments, and humanized mouse models.

Results

Our comprehensive analysis identified the m6A reader protein IGF2BP2 as a critical factor associated with poor prognosis in PDAC, linked to reduced effector cell infiltration and a fibrotic TME. High matrix stiffness in PDAC stabilized IGF2BP2, which subsequently promoted sphingomyelin synthesis via SGMS2 upregulation. This pathway facilitates PD-L1 localization on membrane lipid rafts, enhancing immune evasion. The elastographic properties of PDAC enabled noninvasive screening of patients with overexpressed IGF2BP2/SGMS2. Disrupting sphingomyelin synthesis improved antitumor immunity and suppressed PDAC growth in humanized mice, highlighting immunotherapeutic opportunities for PDAC.

Conclusion

These findings emphasize the critical interplay between extrinsic matrix stiffness and intrinsic IGF2BP2-regulated sphingomyelin synthesis, identifying a promising target for immunotherapeutic strategies in PDAC.

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来源期刊

Gastroenterology 医学-胃肠肝病学

CiteScore

45.60

自引率

2.40%

发文量

4366

审稿时长

26 days

期刊介绍： Gastroenterology is the most prominent journal in the field of gastrointestinal disease. It is the flagship journal of the American Gastroenterological Association and delivers authoritative coverage of clinical, translational, and basic studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. Some regular features of Gastroenterology include original research studies by leading authorities, comprehensive reviews and perspectives on important topics in adult and pediatric gastroenterology and hepatology. The journal also includes features such as editorials, correspondence, and commentaries, as well as special sections like "Mentoring, Education and Training Corner," "Diversity, Equity and Inclusion in GI," "Gastro Digest," "Gastro Curbside Consult," and "Gastro Grand Rounds." Gastroenterology also provides digital media materials such as videos and "GI Rapid Reel" animations. It is abstracted and indexed in various databases including Scopus, Biological Abstracts, Current Contents, Embase, Nutrition Abstracts, Chemical Abstracts, Current Awareness in Biological Sciences, PubMed/Medline, and the Science Citation Index.