The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas
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.
Authors
- José M. Vicencio (ORCID: https://orcid.org/0000-0002-1811-9275)
- Manuel Rodriguez‐Justo (ORCID: https://orcid.org/0000-0001-5007-1761)
- Caitlin McCarthy (ORCID: https://orcid.org/0000-0002-8034-051X)
- Tony Ng (ORCID: https://orcid.org/0000-0003-3894-5619)
- Zhengwen An (ORCID: https://orcid.org/0000-0003-0360-7388)
- Mingzhu Yin (ORCID: https://orcid.org/0000-0002-6964-7131)
- Fengxiang Wei (ORCID: https://orcid.org/0000-0001-7559-2504)
- Sabine Tejpar (ORCID: https://orcid.org/0000-0003-3281-8643)
- Yourae Hong (ORCID: https://orcid.org/0000-0001-6683-433X)
- Teng Pan (ORCID: https://orcid.org/0000-0003-1384-9006)
- Richard Beatson (ORCID: https://orcid.org/0000-0002-0411-932X)
- Giovanna Alfano
- Luigi Dolcetti (ORCID: https://orcid.org/0000-0003-0675-4906)
- Gregory Weitsman (ORCID: https://orcid.org/0000-0002-1313-6279)
- Jinhai Deng (ORCID: https://orcid.org/0000-0002-2899-5332)
- Xiaoping Yang (ORCID: https://orcid.org/0000-0002-6811-4915)
- Christopher J. Tape (ORCID: https://orcid.org/0000-0003-4712-2737)
- James Monypenny
- Joanna C. Porter (ORCID: https://orcid.org/0000-0002-7307-169X)
- Xingang Zhou (ORCID: https://orcid.org/0000-0002-4211-3017)
- Zedong Hu
- Camila Gomes (ORCID: https://orcid.org/0000-0003-2094-8141)
- Rachel Evans (ORCID: https://orcid.org/0000-0002-8853-6920)
- Petra Vlckova (ORCID: https://orcid.org/0000-0001-9633-8492)
- Gang Li (ORCID: https://orcid.org/0000-0003-2144-4631)
- Jin Zhang (ORCID: https://orcid.org/0000-0001-7145-7823)
- Yue Chen (ORCID: https://orcid.org/0000-0002-9529-1626)
- Lifeng Li (ORCID: https://orcid.org/0000-0002-7492-4017)
- Zaoqu Liu (ORCID: https://orcid.org/0000-0002-0452-742X)
- Dan Wang
- Kenrick Ng
Institutions
- AstraZeneca (United Kingdom) (GB)
- University College Hospital (GB)
- Ministry of Education of the People's Republic of China (CN)
- University College London Hospitals NHS Foundation Trust (GB)
- Queen Mary University of London (GB)
- Capital Medical University (CN)
- King's College London (GB)
- Peking University (CN)
- Breast Cancer Now (GB)
- Universitair Ziekenhuis Leuven (BE)
- Cancer Research UK (GB)
- Tianjin Medical University Cancer Institute and Hospital (CN)
- Shenzhen Maternity and Child Healthcare Hospital (CN)
- Peking University Third Hospital (CN)
- CRUK Lung Cancer Centre of Excellence (GB)
- Beijing Ditan Hospital (CN)
- Centre for Inflammation Research (GB)
- First Affiliated Hospital of Zhengzhou University (CN)
- University College London (GB)
- Chongqing Three Gorges University (CN)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1038/s44321-024-00105-2
- Citations
- 5
- Primary Topic
- GDF15 and Related Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 2.35
Funders
- Breast Cancer Now
- Cancer Research UK
- National Institute for Health and Care Research
- China Scholarship Council
- University College London Hospitals NHS Foundation Trust
- Medical Research Council
- UCLH Biomedical Research Centre