Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response.
Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response.
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肾细胞癌的单细胞分析揭示了对肿瘤微环境、细胞起源和治疗反应的见解。
DOI：
10.1073/pnas.2103240118
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发表时间：
2021-06-15
影响因子：
11.1
通讯作者：
Chinnaiyan AM
中科院分区：
文献类型：
--
作者：
Zhang Y;Narayanan SP;Mannan R;Raskind G;Wang X;Vats P;Su F;Hosseini N;Cao X;Kumar-Sinha C;Ellison SJ;Giordano TJ;Morgan TM;Pitchiaya S;Alva A;Mehra R;Cieslik M;Dhanasekaran SM;Chinnaiyan AM
Renal cell carcinomas (RCCs) are heterogeneous malignancies thought to arise from kidney tubular epithelial cells, and clear cell RCC is the most common entity. This study demonstrates that cell atlases generated from benign kidney and two common RCCs using single-cell RNA sequencing can predict putative cells of origin for more than 10 RCC subtypes. A focused analysis of distinct cell-type compartments reveals the potential role of tumor epithelia in promoting immune infiltration and other molecular attributes of the tumor microenvironment. Finally, an observed association between the lack of immunotherapy response and endothelial cell fraction has important clinical implications. The current study, therefore, significantly contributes toward understanding disease ontogenies and the molecular dynamics of tumor epithelia and the microenvironment. Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide insight into the putative cell of origin for RCC subtypes and highlight the important role of the tumor microenvironment in influencing ccRCC biology and response to therapy.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
通讯作者：
Itzkovitz S
影响因子：
11
作者：
Huling J;Yoo JJ
通讯作者：
Yoo JJ
影响因子：
28.2
作者：
Chen PL;Roh W;Reuben A;Cooper ZA;Spencer CN;Prieto PA;Miller JP;Bassett RL;Gopalakrishnan V;Wani K;De Macedo MP;Austin-Breneman JL;Jiang H;Chang Q;Reddy SM;Chen WS;Tetzlaff MT;Broaddus RJ;Davies MA;Gershenwald JE;Haydu L;Lazar AJ;Patel SP;Hwu P;Hwu WJ;Diab A;Glitza IC;Woodman SE;Vence LM;Wistuba II;Amaria RN;Kwong LN;Prieto V;Davis RE;Ma W;Overwijk WW;Sharpe AH;Hu J;Futreal PA;Blando J;Sharma P;Allison JP;Chin L;Wargo JA
通讯作者：
Wargo JA
对肾细胞癌生物学的新见解。
DOI：
10.1016/j.hoc.2011.04.004
发表时间：
2011-08
期刊：
Hematology/oncology clinics of North America
影响因子：
--
作者：
Li L;Kaelin WG Jr
通讯作者：
Kaelin WG Jr
影响因子：
5.9
作者：
Borcherding N;Vishwakarma A;Voigt AP;Bellizzi A;Kaplan J;Nepple K;Salem AK;Jenkins RW;Zakharia Y;Zhang W
通讯作者：
Zhang W