NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy in pancreatic cancer.

IF 12.6 1区医学 Q1 IMMUNOLOGY

Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-10-21 DOI:10.1084/jem.20240766

Daiyong Deng, Habeebunnisa Begum, Tong Liu, Jiangyan Zhang, Qiang Zhang, Ting-Yu Chu, Hong Li, Alexander Lemenze, Mainul Hoque, Patricia Soteropoulos, Pingping Hou

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引用次数: 0

Abstract

Resistance to KRAS therapy in pancreatic ductal adenocarcinoma (PDAC) involves cellular plasticity, particularly the epithelial-to-mesenchymal transition (EMT), which poses challenges for effective targeting. Chronic pancreatitis, a known risk factor for PDAC, elevates TGFβ levels in the tumor microenvironment (TME), promoting resistance to KRAS therapy. Mechanistically, TGFβ induces the formation of a novel protein complex composed of SMAD3, SMAD4, and the nuclear factor NFAT5, triggering EMT and resistance by activating key mediators such as S100A4. Inhibiting NFAT5 attenuates pancreatitis-induced resistance to KRAS inhibition and extends mouse survival. Additionally, TGFβ stimulates PDAC cells to secrete CCL2, recruiting macrophages that contribute to KRAS bypass through paracrine S100A4. Our findings elucidate the role of TGFβ signaling in EMT-associated KRAS therapy resistance and identify NFAT5 as a druggable target. Targeting NFAT5 could disrupt this regulatory network, offering a potential avenue for preventing resistance in PDAC.

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NFAT5 对胰腺癌细胞可塑性驱动的 KRAS 靶向疗法耐药性起着支配作用。

胰腺导管腺癌（PDAC）对KRAS疗法的耐药性涉及细胞可塑性，尤其是上皮细胞向间质转化（EMT），这给有效靶向治疗带来了挑战。慢性胰腺炎是PDAC的一个已知风险因素，它会升高肿瘤微环境（TME）中的TGFβ水平，促进对KRAS疗法的耐药性。从机理上讲，TGFβ会诱导由SMAD3、SMAD4和核因子NFAT5组成的新型蛋白复合物的形成，通过激活S100A4等关键介质引发EMT和耐药性。抑制 NFAT5 可减轻胰腺炎引起的对 KRAS 抑制的抵抗，并延长小鼠的存活时间。此外，TGFβ刺激PDAC细胞分泌CCL2，招募巨噬细胞，巨噬细胞通过旁分泌S100A4促进KRAS旁路。我们的研究结果阐明了TGFβ信号在与EMT相关的KRAS耐药性中的作用，并确定了NFAT5为药物靶点。以 NFAT5 为靶点可以破坏这一调控网络，为防止 PDAC 的耐药性提供潜在的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Experimental Medicine 医学-免疫学

CiteScore

26.60

自引率

1.30%

发文量

189

审稿时长

3-8 weeks

期刊介绍： Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.