Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers
Ryosuke Jikuya, K. 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 Shuch, Laura S. Schmidt, W. Marston Linehan, Hidewaki Nakagawa, Tomohiko Tamura, Hisashi Hasumi
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.