Identification of a novel cancer stem cell subpopulation that promotes progression of human fatal renal cell carcinoma by single-cell RNA-seq analysis

• Published in: International journal of biological sciences 2020-01, Vol.16 (16), p.3149-3162
• Main Authors: Pan, Xiu-Wu, Zhang, Hao, Xu, Da, Chen, Jia-Xin, Chen, Wen-Jin, Gan, Si-Shun, Qu, Fa-Jun, Chu, Chuan-Min, Cao, Jian-Wei, Fan, Ying-Hui, Song, Xu, Ye, Jian-Qing, Zhou, Wang, Cui, Xin-Gang
• Format: Article
• Language: English
• Subjects: Biological properties; Cancer; Cancer therapies; Cell cycle; Cell proliferation; Cell self-renewal; Clustering; Collecting duct; Computer applications; Differentiation; Drug resistance; Feedback loops; Fibroblast growth factor receptors; Gene expression; Gene sequencing; HDAC2 protein; Histone deacetylase; Kidney cancer; Lymphocytes; Malignancy; Medical prognosis; Metastases; Metastasis; Microenvironments; Patients; Pituitary tumor-transforming proteins; Poly(ADP-ribose) polymerase; Positive feedback; Renal cell carcinoma; Research Paper; Ribonucleic acid; RNA; Smooth muscle; Statistical analysis; Statistical methods; Stem cells; Subpopulations; Temporal variations; Transcription factors; Tumors
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.46645

Cancer stem cells (CSCs) are biologically characterized by self-renewal, multi-directional differentiation and infinite proliferation, inducing anti-tumor drug resistance and metastasis. In the present study, we attempted to depict the baseline landscape of CSC-mediated biological properties, knowing that it is vital for tumor evolution, anti-tumor drug selection and drug resistance against fatal malignancy. We performed single-cell RNA sequencing (scRNA-seq) analysis in 15208 cells from a pair of primary and metastatic sites of collecting duct renal cell carcinoma (CDRCC). Cell subpopulations were identified and characterized by t-SNE, RNA velocity, monocle and other computational methods. Statistical analysis of all single-cell sequencing data was performed in R and Python. A CSC population of 1068 cells was identified and characterized, showing excellent differentiation and self-renewal properties. These CSCs positioned as a center of the differentiation process and transformed into CDRCC primary and metastatic cells in spatial and temporal order, and played a pivotal role in promoting the bone destruction process with a positive feedback loop in the bone metastasis microenvironment. In addition, CSC-specific marker genes BIRC5, PTTG1, CENPF and CDKN3 were observed to be correlated with poor prognosis of CDRCC. Finally, we pinpointed that PARP, PIGF, HDAC2, and FGFR inhibitors for effectively targeting CSCs may be the potential therapeutic strategies for CDRCC. The results of the present study may shed new light on the identification of CSCs, and help further understand the mechanism underlying drug resistance, differentiation and metastasis in human CDRCC.