Department of Urology, The Gongli Hospital of Second Military Medical University, Shanghai 200135, China.
Department of Urology, The Third Affiliated Hospital of Second Military Medical University, Shanghai 201805, China.
Int J Biol Sci. 2020 Oct 17;16(16):3149-3162. doi: 10.7150/ijbs.46645. eCollection 2020.
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.
癌症干细胞（CSCs）具有自我更新、多向分化和无限增殖的生物学特性，诱导抗肿瘤药物耐药和转移。在本研究中，我们试图描绘 CSC 介导的生物学特性的基线景观，因为这对于肿瘤进化、抗肿瘤药物选择以及针对致命恶性肿瘤的耐药性至关重要。我们对一对收集管肾细胞癌（CDRCC）的原发和转移部位的 15208 个细胞进行了单细胞 RNA 测序（scRNA-seq）分析。通过 t-SNE、RNA 速度、单核细胞和其他计算方法鉴定和描述细胞亚群。所有单细胞测序数据的统计分析均在 R 和 Python 中进行。鉴定和描述了一个由 1068 个细胞组成的 CSC 群体，显示出良好的分化和自我更新特性。这些 CSCs 定位于分化过程的中心，并按时空顺序转化为 CDRCC 的原发和转移细胞，在骨转移微环境中通过正反馈循环发挥关键作用，促进骨破坏过程。此外，CSC 特异性标记基因 BIRC5、PTTG1、CENPF 和 CDKN3 与 CDRCC 的不良预后相关。最后，我们发现 PARP、PIGF、HDAC2 和 FGFR 抑制剂可能是针对 CSCs 的潜在治疗策略。本研究的结果可能为 CSCs 的鉴定提供新的思路，并有助于进一步了解人类 CDRCC 中耐药性、分化和转移的机制。
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