Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers

Ryosuke Jikuya; Koichi Murakami; Akira Nishiyama; Ikuma Kato; Mitsuko Furuya; Jun Nakabayashi; Jordan A Ramilowski; Haruka Hamanoue; Kazuhiro Maejima; Masashi Fujita; Taku Mitome; Shinji Ohtake; Go Noguchi; Sachi Kawaura; Hisakazu Odaka; Takashi Kawahara; Mitsuru Komeya; Risa Shinoki; Daiki Ueno; Hiroki Ito; Yusuke Ito; Kentaro Muraoka; Narihiko Hayashi; Keiichi Kondo; Noboru Nakaigawa; Koji Hatano; Masaya Baba; Toshio Suda; Tatsuhiko Kodama; Satoshi Fujii; Kazuhide Makiyama; Masahiro Yao; Brian M Shuch; Laura S Schmidt; W Marston Linehan; Hidewaki Nakagawa; Tomohiko Tamura; Hisashi Hasumi

doi:10.1016/j.isci.2022.104463

Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers

iScience. 2022 May 25;25(6):104463. doi: 10.1016/j.isci.2022.104463. eCollection 2022 Jun 17.

Authors

Ryosuke Jikuya^{1

2}, Koichi Murakami^{3

4}, Akira Nishiyama³, Ikuma Kato⁵, Mitsuko Furuya⁵, Jun Nakabayashi⁴, Jordan A Ramilowski⁴, Haruka Hamanoue⁶, Kazuhiro Maejima², Masashi Fujita², Taku Mitome¹, Shinji Ohtake¹, Go Noguchi¹, Sachi Kawaura¹, Hisakazu Odaka¹, Takashi Kawahara¹, Mitsuru Komeya¹, Risa Shinoki¹, Daiki Ueno¹, Hiroki Ito¹, Yusuke Ito¹, Kentaro Muraoka¹, Narihiko Hayashi¹, Keiichi Kondo¹, Noboru Nakaigawa¹, Koji Hatano⁷, Masaya Baba⁸, Toshio Suda⁸, Tatsuhiko Kodama⁹, Satoshi Fujii⁵, Kazuhide Makiyama¹, Masahiro Yao¹, Brian M Shuch¹⁰, Laura S Schmidt^{11

12}, W Marston Linehan¹¹, Hidewaki Nakagawa², Tomohiko Tamura^{3

4}, Hisashi Hasumi¹

Affiliations

¹ Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
² Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
³ Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
⁴ Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan.
⁵ Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
⁶ Clinical Genetics Department, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
⁷ Department of Urology, Osaka University Graduate School of Medicine, Osaka 565-0871 Japan.
⁸ Laboratory of Cancer Metabolism, International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
⁹ Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
¹⁰ Institute of Urologic Oncology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
¹¹ Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
¹² Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.

Abstract

Our understanding of how each hereditary kidney cancer adapts to its tissue microenvironment is incomplete. Here, we present single-cell transcriptomes of 108,342 cells from patient specimens including from six hereditary kidney cancers. The transcriptomes displayed distinct characteristics of the cell of origin and unique tissue microenvironment for each hereditary kidney cancer. Of note, hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated kidney cancer retained some characteristics of proximal tubules, which were completely lost in lymph node metastases and present as an avascular tumor with suppressed T cells and TREM2-high macrophages, leading to immune tolerance. Birt-Hogg-Dubé (BHD)-associated kidney cancer exhibited transcriptomic intratumor heterogeneity (tITH) with increased characteristics of intercalated cells of the collecting duct and upregulation of FOXI1-driven genes, a critical transcription factor for collecting duct differentiation. These findings facilitate our understanding of how hereditary kidney cancers adapt to their tissue microenvironment.

Keywords: Cancer; Cancer systems biology; Human specimen; Microenvironment; Oncology.