The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas.

IF 9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EMBO Molecular Medicine Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI:10.1038/s44321-024-00105-2

Jinhai Deng, Teng Pan, Dan Wang, Yourae Hong, Zaoqu Liu, Xingang Zhou, Zhengwen An, Lifeng Li, Giovanna Alfano, Gang Li, Luigi Dolcetti, Rachel Evans, Jose M Vicencio, Petra Vlckova, Yue Chen, James Monypenny, Camila Araujo De Carvalho Gomes, Gregory Weitsman, Kenrick Ng, Caitlin McCarthy, Xiaoping Yang, Zedong Hu, Joanna C Porter, Christopher J Tape, Mingzhu Yin, Fengxiang Wei, Manuel Rodriguez-Justo, Jin Zhang, Sabine Tejpar, Richard Beatson, Tony Ng

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引用次数: 0

Abstract

Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

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依赖于MondoA的TXNIP/GDF15轴可预测结直肠腺癌的奥沙利铂反应。

化疗是晚期癌症患者的标准治疗方法，越来越多的人认识到化疗能激活宿主免疫反应，从而产生持久的疗效。在这里，我们在结直肠腺癌（CRC）中发现了奥沙利铂诱导的硫氧还蛋白相互作用蛋白（TXNIP），这是一种依赖于蒙多A的肿瘤抑制基因，是生长/分化因子15（GDF15）的负调控因子。GDF15 是 CRC 的负预后因子，能促进调节性 T 细胞（Tregs）的分化，从而抑制 CD8 T 细胞的活化。耐人寻味的是，包括患者衍生肿瘤器官组织在内的多种模型表明，TXNIP 和 GDF15 对奥沙利铂反应性的丧失与疾病晚期或化疗耐药有关，转录组或蛋白质组 GDF15/TXNIP 比率显示出作为预后生物标志物的潜力。这些发现说明了化疗诱导的上皮氧化应激驱动局部免疫重塑使患者获益的潜在共同途径，在难治或晚期病例中会出现这种途径的破坏。

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

EMBO Molecular Medicine 医学-医学：研究与实验

CiteScore

17.70

自引率

0.90%

发文量

105

审稿时长

4-8 weeks

期刊介绍： EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)