Single-cell profiling of the copy-number heterogeneity in colorectal cancer

作     者：Shiyu Song Lin Feng Kexing Xi Zhigang Sun Deyang Kong Zhenkai Luo Wei Pei Haizeng Zhang 

作者机构：Department of Colorectal SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Lab of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular OncologyDepartment of Etiology and CarcinogenesisNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China 

出 版 物：《Chinese Medical Journal》 (中华医学杂志（英文版）)

年 卷 期：2023年第136卷第6期

页      面：707-718页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：Somatic copy number alteration Microsatellite stable Colorectal cancer Single cell RNA-sequencing Intra-tumor genetic heterogeneity 

摘      要：Background:With functionally heterogeneous cells,tumors comprise a complex ecosystem to promote tumor adaptability and evolution under strong selective pressure from the given microenvironment.Diversifying tumor cells or intra-tumor heterogeneity is essential for tumor growth,invasion,and immune evasion.However,no reliable method to classify tumor cell subtypes is yet available.In this study,we introduced the single-cell sequencing combined with copy number characteristics to identify the types of tumor cells in microsatellite stable(MSS)colorectal cancer(CRC).Methods:To characterize the somatic copy number alteration(SCNA)of MSS CRC in a single cell profile,we analyzed 26 tissue samples from 19 Korean patients(GSE132465,the Samsung Medical Center[SMC]dataset)and then verified our findings with 15 tissue samples from five Belgian patients(GSE144735,the Katholieke Universiteit Leuven 3[KUL3]dataset).The Cancer Genome Atlas(TCGA)cohort,GSE39582 cohort,and National Cancer Center(NCC)cohort(24 MSS CRC patients were enrolled in this study between March 2017 and October 2017)were used to validate the clinical features of prognostic signatures.Results:We employed single cell RNA-sequencing data to identify three types of tumor cells in MSS CRC by their SCNA characteristics.Among these three types of tumor cells,C1 and C3 had a higher SCNA burden;C1 had significant chromosome 13 and 20 amplification,whereas C3 was the polar opposite of C1,which exhibited deletion in chromosome 13 and 20.The three types of tumor cells exhibited various functions in the tumor microenvironment and harbored different mutations.C1 and C2 were linked to the immune response and hypoxia,respectively,while C3 was critical for cell adhesion activity and tumor angiogenesis.Additionally,one gene(OLFM4)was identified as epithelium-specific biomarker of better prognosis of CRC(TCGA cohort:P=0.0110;GSE39582 cohort:P=0.0098;NCC cohort:P=0.0360).Conclusions:On the basis of copy number characteristics,we illustrated tumor heterogeneity in MSS CRC and identified three types of tumor cells with distinct roles in tumor microenvironment.By understanding heterogeneity in the intricate tumor microenvironment,we gained an insight into the mechanisms of tumor evolution,which may support the development of therapeutic strategies.