EMBO Molecular Medicine (Aug 2024)

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

  • 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

DOI
https://doi.org/10.1038/s44321-024-00105-2
Journal volume & issue
Vol. 16, no. 9
pp. 2080 – 2108

Abstract

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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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