| Title | Single-cell transcriptomic profiling unravels the adenoma-initiation role of protein tyrosine kinases during colorectal tumorigenesis |
| Authors | Zheng, Xiaobo Song, Jinen Yu, Chune Zhou, Zongguang Liu, Xiaowei Yu, Jing Xu, Guangchao Yang, Jiqiao He, Xiujing Bai, Xin Luo, Ya Bao, Yu Li, Huifang Yang, Lie Xu, Mingqing Song, Nan Su, Xiaodong Xu, Jie Ma, Xuelei Shi, Hubing |
| Affiliation | Sichuan Univ, West China Hosp, Lab Integrat Med, Clin Res Ctr Breast,State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China Collaborat Innovat Ctr, Chengdu 610041, Sichuan, Peoples R China Sichuan Univ, West China Hosp, Frontier Sci Ctr Dis Mol Network, Chengdu 610041, Sichuan, Peoples R China Sichuan Univ, Inst Digest Surg, Chengdu 610041, Sichuan, Peoples R China Sichuan Univ, Dept Gastrointestinal Surg, West China Hosp, West China Sch Med, Chengdu 610041, Sichuan, Peoples R China Sichuan Univ, West China Hosp, Tesearch Core Facil, Chengdu 610041, Sichuan, Peoples R China Sichuan Univ, West China Hosp, State Key Lab Biotherapy & Canc Ctr, Dept Gastrointestinal Surg, Chengdu 610041, Sichuan, Peoples R China Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China Sichuan Univ, West China Hosp, Dept Liver Surg, Chengdu 610041, Sichuan, Peoples R China Capital Med Univ, Beijing Friendship Hosp, Beijing Inst Trop Med, Beijing 100050, Peoples R China Peking Univ, Biomed Pioneering Innovat Ctr BIOPIC, Beijing 100871, Peoples R China Peking Univ, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China Fudan Univ, Zhongshan Xuhui Hosp, Inst Biol Sci, Shanghai 200032, Peoples R China Sichuan Univ, West China Hosp, Canc Ctr, Biotherapy State Key Lab Biotherapy,Dept Biothera, Chengdu 610041, Sichuan, Peoples R China |
| Keywords | CANCER HETEROGENEITY EVOLUTION COLON PHYLOGENY |
| Issue Date | 28-Feb-2022 |
| Publisher | SIGNAL TRANSDUCTION AND TARGETED THERAPY |
| Abstract | 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. |
| URI | http://hdl.handle.net/20.500.11897/638754 |
| ISSN | 2095-9907 |
| DOI | 10.1038/s41392-022-00881-8 |
| Indexed | SCI(E) |
| Appears in Collections: | 生物医学前沿创新中心 其他实验室 |
