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:10.1038/s44321-024-00105-2

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 McCarthyXiaoping Yang, Zedong Hu, Joanna C. Porter, Christopher J. Tape, Mingzhu Yin, Fengxiang Wei, Manuel Rodriguez-Justo, Jin Zhang, Sabine Tejpar, Richard Beatson^*, Tony Ng^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Pages (from-to)	2080-2108
Number of pages	29
Journal	EMBO Molecular Medicine
Volume	16
Issue number	9
DOIs	https://doi.org/10.1038/s44321-024-00105-2
Publication status	Published - 12 Sept 2024

Keywords

Colorectal Cancer
Functional Biomarker
GDF15
Oxaliplatin
TXNIP

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s44321-024-00105-2

Cite this

Deng, J., Pan, T., Wang, D., Hong, Y., Liu, Z., Zhou, X., An, Z., Li, L., Alfano, G., Li, G., Dolcetti, L., Evans, R., Vicencio, J. M., Vlckova, P., Chen, Y., Monypenny, J., Gomes, C. A. D. C., Weitsman, G., Ng, K., ... Ng, T. (2024). The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas. EMBO Molecular Medicine, 16(9), 2080-2108. https://doi.org/10.1038/s44321-024-00105-2

@article{b353abfef752405bbf522deeffa7ad7e,

title = "The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas",

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 = "Colorectal Cancer, Functional Biomarker, GDF15, Oxaliplatin, TXNIP",

author = "Jinhai Deng and Teng Pan and Dan Wang and Yourae Hong and Zaoqu Liu and Xingang Zhou and Zhengwen An and Lifeng Li and Giovanna Alfano and Gang Li and Luigi Dolcetti and Rachel Evans and Vicencio, {Jose M.} and Petra Vlckova and Yue Chen and James Monypenny and Gomes, {Camila Araujo De Carvalho} and Gregory Weitsman and Kenrick Ng and Caitlin McCarthy and Xiaoping Yang and Zedong Hu and Porter, {Joanna C.} and Tape, {Christopher J.} and Mingzhu Yin and Fengxiang Wei and Manuel Rodriguez-Justo and Jin Zhang and Sabine Tejpar and Richard Beatson and Tony Ng",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = sep,

day = "12",

doi = "10.1038/s44321-024-00105-2",

language = "English",

volume = "16",

pages = "2080--2108",

journal = "EMBO Molecular Medicine",

issn = "1757-4676",

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number = "9",

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Deng, J, Pan, T, Wang, D, Hong, Y, Liu, Z, Zhou, X, An, Z, Li, L, Alfano, G, Li, G, Dolcetti, L, Evans, R, Vicencio, JM, Vlckova, P, Chen, Y, Monypenny, J, Gomes, CADC, Weitsman, G, Ng, K, McCarthy, C , Yang, X, Hu, Z, Porter, JC, Tape, CJ, Yin, M, Wei, F, Rodriguez-Justo, M, Zhang, J, Tejpar, S, Beatson, R & Ng, T 2024, 'The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas', EMBO Molecular Medicine, vol. 16, no. 9, pp. 2080-2108. https://doi.org/10.1038/s44321-024-00105-2

TY - JOUR

T1 - The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas

AU - Deng, Jinhai

AU - Pan, Teng

AU - Wang, Dan

AU - Hong, Yourae

AU - Liu, Zaoqu

AU - Zhou, Xingang

AU - An, Zhengwen

AU - Li, Lifeng

AU - Alfano, Giovanna

AU - Li, Gang

AU - Dolcetti, Luigi

AU - Evans, Rachel

AU - Vicencio, Jose M.

AU - Vlckova, Petra

AU - Chen, Yue

AU - Monypenny, James

AU - Gomes, Camila Araujo De Carvalho

AU - Weitsman, Gregory

AU - Ng, Kenrick

AU - McCarthy, Caitlin

AU - Yang, Xiaoping

AU - Hu, Zedong

AU - Porter, Joanna C.

AU - Tape, Christopher J.

AU - Yin, Mingzhu

AU - Wei, Fengxiang

AU - Rodriguez-Justo, Manuel

AU - Zhang, Jin

AU - Tejpar, Sabine

AU - Beatson, Richard

AU - Ng, Tony

PY - 2024/9/12

Y1 - 2024/9/12

N2 - 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.

AB - 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.

KW - Colorectal Cancer

KW - Functional Biomarker

KW - GDF15

KW - Oxaliplatin

KW - TXNIP

UR - http://www.scopus.com/inward/record.url?scp=85200384386&partnerID=8YFLogxK

U2 - 10.1038/s44321-024-00105-2

DO - 10.1038/s44321-024-00105-2

M3 - Article

C2 - 39103698

AN - SCOPUS:85200384386

SN - 1757-4676

VL - 16

SP - 2080

EP - 2108

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 9

ER -

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

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Keywords

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