单位：[1]Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041 Chengdu, Sichuan, China四川大学华西医院[2]Frontier Science Center for Disease Molecular Network, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China四川大学华西医院[3]Institute of Digestive Surgery, Sichuan University, and Department of Gastrointestinal Surgery, West China Hospital, West China School of Medicine, Sichuan University, 610041 Chengdu, Sichuan, China四川大学华西医院[4]Research Core Facility, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China四川大学华西医院[5]Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041 Chengdu, Sichuan, China四川大学华西医院[6]Department of Liver Surgery, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China四川大学华西医院[7]Beijing Institute of Tropical Medicine, Beijing Friendship Hospital, Capital Medical University, 100050 Beijing, China首都医科大学附属北京友谊医院[8]Biomedical Pioneering Innovation Center (BIOPIC), and State Key Laboratory of Protein and Plant Gene Research, Peking University, 100871 Beijing, China[9]Institutes of Biological Sciences, Zhongshan-Xuhui Hospital, Fudan University, 200032 Shanghai, China and 10Department of biotherapy, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China四川大学华西医院
The adenoma-carcinoma sequence is a well-accepted roadmap for the development of sporadic colorectal cancer. However, cellular heterogeneity in aberrant epithelial cells limits our understanding of carcinogenesis in colorectal tissues. Here, we performed a single-cell RNA sequencing survey of 54,788 cells from patient-matched tissue samples, including blood, normal tissue, para-cancer, polyp, and colorectal cancer. At each stage of carcinogenesis, we characterized cell types, transcriptional signatures, and differentially expressed genes of distinct cell populations. The molecular signatures of epithelial cells at normal, benign, and malignant stages were defined at the single-cell scale. Adenoma and carcinoma precursor cell populations were identified and characterized followed by validation with large cohort biopsies. Protein tyrosine kinases (PTKs) BMX and HCK were identified as potential drivers of adenoma initiation. Specific BMX and HCK upregulations were observed in adenoma precursor cell populations from normal and adenoma biopsies. Overexpression of BMX and HCK significantly promoted colorectal epithelial cell proliferation. Importantly, in the organoid culture system, BMX and HCK upregulations resulted in the formation of multilayered polyp-like buds protruding towards the organoid lumen, mimicking the pathological polyp morphology often observed in colorectal cancer. Molecular mechanism analysis revealed that upregulation of BMX or HCK activated the JAK-STAT pathway. In conclusion, our work improved the current knowledge regarding colorectal epithelial evolution during carcinogenesis at the single-cell resolution. These findings may lead to improvements in colorectal cancer diagnosis and treatment.
基金：
National Key Research and Development Program of China [2016YFC0906000 [2016YFC0906003]]; National Natural Science Foundation of China [81773752, 81803574, 81902686, 81801980]; Key Program of the Science and Technology Bureau of Sichuan [2021YFSY0007]; 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZYYC20013]
第一作者单位：[1]Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041 Chengdu, Sichuan, China[2]Frontier Science Center for Disease Molecular Network, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China
共同第一作者：
通讯作者：
通讯机构：[1]Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041 Chengdu, Sichuan, China[2]Frontier Science Center for Disease Molecular Network, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China
推荐引用方式(GB/T 7714)：
Zheng Xiaobo,Song Jinen,Yu Chune,et al.Single-cell transcriptomic profiling unravels the adenoma-initiation role of protein tyrosine kinases during colorectal tumorigenesis[J].SIGNAL TRANSDUCTION and TARGETED THERAPY.2022,7(1):doi:10.1038/s41392-022-00881-8.
APA：
Zheng, Xiaobo,Song, Jinen,Yu, Chune,Zhou, Zongguang,Liu, Xiaowei...&Shi, Hubing.(2022).Single-cell transcriptomic profiling unravels the adenoma-initiation role of protein tyrosine kinases during colorectal tumorigenesis.SIGNAL TRANSDUCTION and TARGETED THERAPY,7,(1)
MLA：
Zheng, Xiaobo,et al."Single-cell transcriptomic profiling unravels the adenoma-initiation role of protein tyrosine kinases during colorectal tumorigenesis".SIGNAL TRANSDUCTION and TARGETED THERAPY 7..1(2022)
医学