Dynamic heterogeneity of colorectal cancer during progression revealed clinical risk-associated cell types and regulations in single-cell resolution and spatial context  

作　　者：Haoxian Ke Zhihao Li Peisi Li Shubiao Ye Junfeng Huang Tuo Hu Chi Zhang Ming Yuan Yuan Chen Xianrui Wu Ping Lan 

机构地区：[1]Department of General Surgery(Colorectal Surgery),The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [2]Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases,Guangdong Institute of Gastroenterology,The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [3]School of Medicine,Sun Yat-sen University,Shenzhen,Guangdong,P.R.China

出　　处：《Gastroenterology Report》2023年第1期365-384,共20页胃肠病学报道（英文）

基　　金：supported by the National Key Research and Development Program of China[grant number 2022YFA1304000];the National Natural Science Foundation of China Key Joint Project[grant number U21A20344];the National Natural Science Foundation of China[grant number 81970452];the Program of Guangdong Provincial Clinical Research Center for Digestive Diseases[grant number 2020B1111170004];the Science and Technology Program of Shenzhen,China[grant number JCYJ20190807161807867];the Starting Funding of Faculty from Sun Yat-sen University[grant number 2021276];the Regional Joint Project for Basic and Applied Basic Research Fund of Guangdong Province[grant number 2022A1515111043];the Science and Technology Planning Project of Guangzhou City[grant number 2023A04J01601],and National Key Clinical Discipline.

摘　　要：Background:Tumor heterogeneity is contributed by tumor cells and the microenvironment.Dynamics of tumor heterogeneity during colorectal cancer(CRC)progression have not been elucidated.Methods:Eight single-cell RNA sequencing(scRNA-seq)data sets of CRC were included.Milo was utilized to reveal the differential abundance of cell clusters during progression.The differentiation trajectory was imputed by using the Palantir algorithm and metabolic states were assessed by using scMetabolism.Three spatial transcription sequencing(ST-seq)data sets of CRC were used to validate cell-type abundances and colocalization.Cancer-associated regulatory hubs were defined as communication networks affecting tumor biological behaviors.Finally,quantitative reverse transcription polymerase chain reaction and immunohistochemistry staining were performed for validation.Results:TM4SF1t,SOX4t,and MKI67t tumor cells;CXCL12t cancer-associated fibroblasts;CD4t resident memory T cells;Treg;IgAt plasma cells;and several myeloid subsets were enriched in stage IV CRC,most of which were associated with overall survival of patients.Trajectory analysis indicated that tumor cells from patients with advanced-stage CRC were less differentiated,when metabolic heterogeneity showed a highest metabolic signature in terminal states of stromal cells,T cells,and myeloid cells.Moreover,ST-seq validated cell-type abundance in a spatial context and also revealed the correlation of immune infiltration between tertiary lymphoid structures and tumors followed by validation in our cohort.Importantly,analysis of cancer-associated regulatory hubs revealed a cascade of activated pathways including leukocyte apoptotic process,MAPK pathway,myeloid leukocyte differentiation,and angiogenesis during CRC progression.Conclusions:Tumor heterogeneity was dynamic during progression,with the enrichment of immunosuppressive Treg,myeloid cells,and fibrotic cells.The differential state of tumor cells was associated with cancer staging.Assessment of cancer-associated regulatory hubs

关 键 词：colorectal cancer tumor heterogeneity tumor progression single-cell RNA sequencing spatial transcription sequencing 

分 类 号：R73[医药卫生—肿瘤]