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Int J Biol Sci 2023; 19(11):3526-3543. doi:10.7150/ijbs.84781 This issue Cite

Research Paper

Unraveling Colorectal Cancer and Pan-cancer Immune Heterogeneity and Synthetic Therapy Response Using Cuproptosis and Hypoxia Regulators by Multi-omic Analysis and Experimental Validation

Pei-Cheng Jiang1,2, Jin Fan3, Chun-Dong Zhang4,5, Ming-Hua Bai1,2, Quan-Quan Sun1,2, Qian-Ping Chen1,2,6, Wei Mao1,2,6, Bu-Fu Tang7, Hui-Yin Lan1,2,6, Yang-Yang Zhou8, Ji Zhu1,2,6✉

1. Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
2. Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
3. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
4. Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
5. Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
6. Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.
7. Department of Radiation Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.
8. Department of Oncology, Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

✉ Corresponding author: Prof. Ji Zhu, Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China. Tel: +86-13501978674; Email: leoon.zhucom.

Citation:
Jiang PC, Fan J, Zhang CD, Bai MH, Sun QQ, Chen QP, Mao W, Tang BF, Lan HY, Zhou YY, Zhu J. Unraveling Colorectal Cancer and Pan-cancer Immune Heterogeneity and Synthetic Therapy Response Using Cuproptosis and Hypoxia Regulators by Multi-omic Analysis and Experimental Validation. Int J Biol Sci 2023; 19(11):3526-3543. doi:10.7150/ijbs.84781. https://www.ijbs.com/v19p3526.htm
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Abstract

Graphic abstract

Cuproptosis, a new type of programmed cell death (PCD), is closely related to cellular tricarboxylic acid cycle and cellular respiration, while hypoxia can modulate PCD. However, their combined contribution to tumor subtyping remains unexplored. Here, we applied a multi-omics approach to classify TCGA_COADREAD based on cuproptosis and hypoxia. The classification was validated in three colorectal cancer (CRC) cohorts and extended to a pan-cancer analysis. The results demonstrated that pan-cancers, including CRC, could be divided into three distinct subgroups (cuproptosis-hypoxia subtypes, CHSs): CHS1 had active metabolism and poor immune infiltration but low fibrosis; CHS3 had contrasting characteristics with CHS1; CHS2 was intermediate. CHS1 may respond well to cuproptosis inducers, and CHS3 may benefit from a combination of immunotherapy and anti-fibrosis/anti-hypoxia therapies. In CRC, the CHSs also showed a significant difference in prognosis and sensitivity to classic drugs. Organoid-based drug sensitivity assays validated the results of transcriptomics. Cell-based assays indicated that masitinib and simvastatin had specific effects on CHS1 and CHS3, respectively. A user-friendly website based on the classifier was developed (https://fan-app.shinyapps.io/chs_classifier/) for accessibility. Overall, the classifier based on cuproptosis and hypoxia was applicable to most pan-cancers and could aid in personalized cancer therapy.

Keywords: cuproptosis, hypoxia, clustering, colorectal cancer, precision treatment

Citation styles

APA
Jiang, P.C., Fan, J., Zhang, C.D., Bai, M.H., Sun, Q.Q., Chen, Q.P., Mao, W., Tang, B.F., Lan, H.Y., Zhou, Y.Y., Zhu, J. (2023). Unraveling Colorectal Cancer and Pan-cancer Immune Heterogeneity and Synthetic Therapy Response Using Cuproptosis and Hypoxia Regulators by Multi-omic Analysis and Experimental Validation. International Journal of Biological Sciences, 19(11), 3526-3543. https://doi.org/10.7150/ijbs.84781.

ACS
Jiang, P.C.; Fan, J.; Zhang, C.D.; Bai, M.H.; Sun, Q.Q.; Chen, Q.P.; Mao, W.; Tang, B.F.; Lan, H.Y.; Zhou, Y.Y.; Zhu, J. Unraveling Colorectal Cancer and Pan-cancer Immune Heterogeneity and Synthetic Therapy Response Using Cuproptosis and Hypoxia Regulators by Multi-omic Analysis and Experimental Validation. Int. J. Biol. Sci. 2023, 19 (11), 3526-3543. DOI: 10.7150/ijbs.84781.

NLM
Jiang PC, Fan J, Zhang CD, Bai MH, Sun QQ, Chen QP, Mao W, Tang BF, Lan HY, Zhou YY, Zhu J. Unraveling Colorectal Cancer and Pan-cancer Immune Heterogeneity and Synthetic Therapy Response Using Cuproptosis and Hypoxia Regulators by Multi-omic Analysis and Experimental Validation. Int J Biol Sci 2023; 19(11):3526-3543. doi:10.7150/ijbs.84781. https://www.ijbs.com/v19p3526.htm

CSE
Jiang PC, Fan J, Zhang CD, Bai MH, Sun QQ, Chen QP, Mao W, Tang BF, Lan HY, Zhou YY, Zhu J. 2023. Unraveling Colorectal Cancer and Pan-cancer Immune Heterogeneity and Synthetic Therapy Response Using Cuproptosis and Hypoxia Regulators by Multi-omic Analysis and Experimental Validation. Int J Biol Sci. 19(11):3526-3543.

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