The MondoA-dependent TXNIP/GDF15 Axis Predicts Oxaliplatin Response in Colorectal Adenocarcinomas

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2024 Aug 5

PMID 39103698

Authors

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

Affiliations

Soon will be listed here.

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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