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 Jiang; Jin Fan; Chun-Dong Zhang; Ming-Hua Bai; Quan-Quan Sun; Qian-Ping Chen; Wei Mao; Bu-Fu Tang; Hui-Yin Lan; Yang-Yang Zhou; Ji Zhu

doi:10.7150/ijbs.84781

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 Jul 9;19(11):3526-3543. doi: 10.7150/ijbs.84781. eCollection 2023.

Authors

Pei-Cheng Jiang^{1

2}, Jin Fan³, Chun-Dong Zhang^{4

5}, Ming-Hua Bai^{1

2}, Quan-Quan Sun^{1

2}, Qian-Ping Chen^{1

2

6}, Wei Mao^{1

2

6}, Bu-Fu Tang⁷, Hui-Yin Lan^{1

2

6}, Yang-Yang Zhou⁸, Ji Zhu^{1

2

6}

Affiliations

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.

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: clustering; colorectal cancer; cuproptosis; hypoxia; precision treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Gene Expression Profiling
Humans
Hypoxia
Immunotherapy
Multiomics*