Chemotherapeutic regulation of the ROS/MondoA-dependent TXNIP/GDF15 axis; and derivation of a new organoid metric as a predictive biomarker

  1. Jinhai Deng
  2. Teng Pan
  3. Yourae Hong
  4. Zaoqu Liu
  5. Xingang Zhou
  6. Zhengwen An
  7. Lifeng Li
  8. Giovanna Alfano
  9. Gang Li
  10. Luigi Dolcetti
  11. Rachel Evans
  12. Jose M Vicencio
  13. Petra Vlckova
  14. Yue Chen
  15. James Monypenny
  16. Camila Araujo De Carvalho Gomes
  17. Kenrick Ng
  18. Caitlin McCarthy
  19. Xiaoping Yang
  20. Zedong Hu
  21. Joanna C. Porter
  22. Christopher J Tape
  23. Mingzhu Yin
  24. Manuel Rodriguez-Justo
  25. Sabine Tejpar
  26. Richard Beatson
  27. Tony Ng
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Abstract

Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognised to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify chemotherapy-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), through CD48 ligation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that loss of TXNIP/GDF15 axis functionality 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 stress drives local immune remodelling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

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