Single-cell RNA-seq integrated with multi-omics reveals SERPINE2 as a target for metastasis in advanced renal cell carcinoma.
Single-cell RNA-seq integrated with multi-omics reveals SERPINE2 as a target for metastasis in advanced renal cell carcinoma.
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DOI：
10.1038/s41419-023-05566-w
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发表时间：
2023-01-16
影响因子：
9
通讯作者：
Cui, Xin-gang
中科院分区：
文献类型：
--
作者：
Chen, Wen-jin;Dong, Ke-qin;Pan, Xiu-wu;Gan, Si-shun;Xu, Da;Chen, Jia-xin;Chen, Wei-jie;Li, Wen-yan;Wang, Yu-qi;Zhou, Wang;Rini, Brian;Cui, Xin-gang
在晚期肾细胞癌(RCC)中，肿瘤的生长、转移和治疗反应受到肿瘤及其微环境(TME)的调节。然而，肾癌进展过程中基因组、转录和表观遗传变化的机制尚未完全确定。本研究从8例肾癌患者的组织标本中获得单细胞RNA测序(scRNA-seq)数据，其中包括两对匹配的原发灶和转移灶(淋巴结)，以及Hi-C、高通量转座可及染色质(ATAC-seq)和肾癌(Caki-1)和人肾小管上皮细胞系(HK-2)之间的RNA测序(RNA-seq)。已识别的靶点在临床组织样本(407例肾癌患者的微阵列，TMA-30和TMA-2020)中得到验证，其功能通过体外和体内实验通过敲除或过表达进一步验证。我们分析了30514个恶性细胞和14762个非恶性细胞的转录本。综合多组学分析表明，恶性细胞和TME在肾癌中起关键作用。基质细胞和免疫细胞的表达程序在样本中是一致的，而恶性肿瘤细胞表达的程序与缺氧、细胞周期、上皮分化和两种不同的转移模式有关。层级结构的比较表明，Serpine2与这些NNMF表达程序相关，同时针对开关间隔。Serpine2在肾癌组织中高表达，在癌旁组织和HK-2细胞中低表达。Serpine2基因敲除显著抑制肾癌细胞的生长和侵袭，而Serpine2过表达则显著促进RCC细胞的体外和体内转移。此外，Serpine2还可以激活上皮细胞-间充质细胞转化途径。上述结果表明，不同的恶性细胞和TME的表达模式在肾癌的进展中起着明显的作用。Serpine2被认为是抑制晚期肾癌转移的潜在治疗靶点。
Tumor growth, metastasis and therapeutic response are believed to be regulated by the tumor and its microenvironment (TME) in advanced renal cell carcinoma (RCC). However, the mechanisms underlying genomic, transcriptomic and epigenetic alternations in RCC progression have not been completely defined. In this study, single-cell RNA-sequencing (scRNA-seq) data were obtained from eight tissue samples of RCC patients, including two matched pairs of primary and metastatic sites (lymph nodes), along with Hi-C, transposable accessible chromatin by high-throughput (ATAC-seq) and RNA-sequencing (RNA-seq) between RCC (Caki-1) and human renal tubular epithelial cell line (HK-2). The identified target was verified in clinical tissue samples (microarray of 407 RCC patients, TMA-30 and TMA-2020), whose function was further validated by in vitro and in vivo experiments through knockdown or overexpression. We profiled transcriptomes of 30514 malignant cells, and 14762 non-malignant cells. Comprehensive multi-omics analysis revealed that malignant cells and TME played a key role in RCC. The expression programs of stromal cells and immune cells were consistent among the samples, whereas malignant cells expressed distinct programs associated with hypoxia, cell cycle, epithelial differentiation, and two different metastasis patterns. Comparison of the hierarchical structure showed that SERPINE2 was related to these NNMF expression programs, and at the same time targeted the switched compartment. SERPINE2 was highly expressed in RCC tissues and lowly expressed in para-tumor tissues or HK-2 cell line. SERPINE2 knockdown markedly suppressed RCC cell growth and invasion, while SERPINE2 overexpression dramatically promoted RCC cell metastasis both in vitro and in vivo. In addition, SERPINE2 could activate the epithelial-mesenchymal transition pathway. The above findings demonstrated that the role of distinct expression patterns of malignant cells and TME played a distinct role in RCC progression. SERPINE2 was identified as a potential therapeutic target for inhibiting metastasis in advanced RCC.
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影响因子：
64.5
作者：
Chen B;Scurrah CR;McKinley ET;Simmons AJ;Ramirez-Solano MA;Zhu X;Markham NO;Heiser CN;Vega PN;Rolong A;Kim H;Sheng Q;Drewes JL;Zhou Y;Southard-Smith AN;Xu Y;Ro J;Jones AL;Revetta F;Berry LD;Niitsu H;Islam M;Pelka K;Hofree M;Chen JH;Sarkizova S;Ng K;Giannakis M;Boland GM;Aguirre AJ;Anderson AC;Rozenblatt-Rosen O;Regev A;Hacohen N;Kawasaki K;Sato T;Goettel JA;Grady WM;Zheng W;Washington MK;Cai Q;Sears CL;Goldenring JR;Franklin JL;Su T;Huh WJ;Vandekar S;Roland JT;Liu Q;Coffey RJ;Shrubsole MJ;Lau KS
通讯作者：
Lau KS
影响因子：
19
作者：
Bakir B;Chiarella AM;Pitarresi JR;Rustgi AK
通讯作者：
Rustgi AK
影响因子：
64.8
作者：
Helmink BA;Reddy SM;Gao J;Zhang S;Basar R;Thakur R;Yizhak K;Sade-Feldman M;Blando J;Han G;Gopalakrishnan V;Xi Y;Zhao H;Amaria RN;Tawbi HA;Cogdill AP;Liu W;LeBleu VS;Kugeratski FG;Patel S;Davies MA;Hwu P;Lee JE;Gershenwald JE;Lucci A;Arora R;Woodman S;Keung EZ;Gaudreau PO;Reuben A;Spencer CN;Burton EM;Haydu LE;Lazar AJ;Zapassodi R;Hudgens CW;Ledesma DA;Ong S;Bailey M;Warren S;Rao D;Krijgsman O;Rozeman EA;Peeper D;Blank CU;Schumacher TN;Butterfield LH;Zelazowska MA;McBride KM;Kalluri R;Allison J;Petitprez F;Fridman WH;Sautès-Fridman C;Hacohen N;Rezvani K;Sharma P;Tetzlaff MT;Wang L;Wargo JA
通讯作者：
Wargo JA
影响因子：
11.2
作者：
Fayard, Berengere;Bianchi, Fabrizio;Monard, Denis
通讯作者：
Monard, Denis
影响因子：
4.6
作者：
Acosta, Helena;Iliev, Dobromir;Pera, Edgar M.
通讯作者：
Pera, Edgar M.