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
Affiliations
- Jinhai Deng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Teng Pan
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Dan Wang
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Yourae Hong
- Digestive Oncology Unit and Centre for Human Genetics, Universitair Ziekenhuis (UZ) Leuven
- Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University
- Xingang Zhou
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University
- Zhengwen An
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Lifeng Li
- Internet Medical and System Applications of National Engineering Laboratory
- Giovanna Alfano
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Gang Li
- Department of General Surgery, Peking University Third Hospital
- Luigi Dolcetti
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Rachel Evans
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Jose M Vicencio
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Petra Vlckova
- Cell Communication Lab, UCL Cancer Institute
- Yue Chen
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London
- James Monypenny
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Camila Araujo De Carvalho Gomes
- UCL Cancer Institute, University College London
- Gregory Weitsman
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Kenrick Ng
- Department of Medical Oncology, University College London Hospitals NHS Foundation Trust
- Caitlin McCarthy
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Xiaoping Yang
- Centre of Excellence for Mass Spectrometry, Proteomics Facility, The James Black Centre, King’s College London
- Zedong Hu
- Digestive Oncology Unit and Centre for Human Genetics, Universitair Ziekenhuis (UZ) Leuven
- Joanna C Porter
- Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London (UCL)
- Christopher J Tape
- Cell Communication Lab, UCL Cancer Institute
- Mingzhu Yin
- Clinical Research Centre (CRC), Medical Pathology Centre (MPC), Cancer Early Detection and Treatment Centre (CEDTC), Translational Medicine Research Centre (TMRC), Chongqing University Three Gorges Hospital, Chongqing University
- Fengxiang Wei
- Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College)
- Manuel Rodriguez-Justo
- Department of Histopathology, University College London Hospital
- Jin Zhang
- 3rd Department of Breast Cancer Prevention, Treatment and Research Centre
- Sabine Tejpar
- Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College)
- Richard Beatson
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- Tony Ng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London
- DOI
- https://doi.org/10.1038/s44321-024-00105-2
- Journal volume & issue
-
Vol. 16,
no. 9
pp. 2080 – 2108
Abstract
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.
Keywords
