Dynamic heterogeneity of colorectal cancer during progression revealed clinical risk-associated cell types and regulations in single-cell resolution and spatial context
Haoxian Ke1
Zhihao Li1
Peisi Li2
Shubiao Ye3
Junfeng Huang1
Tuo Hu1
Chi Zhang1
Ming Yuan1
Yuan Chen4
Xianrui Wu1
Ping Lan1
1.Department of General Surgery(Colorectal Surgery),The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China;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.China2.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;School of Medicine,Sun Yat-sen University,Shenzhen,Guangdong,P.R.China3.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.China4.School of Medicine,Sun Yat-sen University,Shenzhen,Guangdong,P.R.China
摘要：Background:Tumor heterogeneity is contributed by tumor cells and the microenvironment.Dynamics of tumor heterogeneity dur-ing 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 meta-bolic states were assessed by using scMetabolism.Three spatial transcription sequencing(ST-seq)data sets of CRC were used to vali-date 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 stain-ing were performed for validation.
Results:TM4SF1+,SOX4+,and MKI67+tumor cells;CXCL12+cancer-associated fibroblasts;CD4+resident memory T cells;Treg;IgA+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 meta-bolic 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 reg-ulatory hubs suggested impaired antitumor immunity and increased metastatic ability during CRC progression.
机标关键词：contextclinicalspatialdynamiccancercolorectalduringheterogeneity
论文发表日期：2024-02-28
在线出版日期：2026-07-17（本平台首次上网日期，不代表文献的发表时间）
页数：20( 13-32 )
英文信息