Multi-tumor analysis of cancer-stroma interactomes of patient-derived xenografts unveils the unique homeostatic process in renal cell carcinomas
Kuniyo Sueyoshi,
Daisuke Komura,
Hiroto Katoh,
Asami Yamamoto,
Takumi Onoyama,
Tsuyoshi Chijiwa,
Takayuki Isagawa,
Mariko Tanaka,
Hiroshi Suemizu,
Masato Nakamura,
Yohei Miyagi,
Hiroyuki Aburatani,
Shumpei Ishikawa
Affiliations
Kuniyo Sueyoshi
Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Experimental Research Buliding, 12thFloor, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8654, Japan; Department of Thoracic Surgery, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Daisuke Komura
Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Experimental Research Buliding, 12thFloor, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8654, Japan; Corresponding author
Hiroto Katoh
Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Experimental Research Buliding, 12thFloor, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8654, Japan
Asami Yamamoto
Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Experimental Research Buliding, 12thFloor, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8654, Japan
Takumi Onoyama
Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Experimental Research Buliding, 12thFloor, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8654, Japan; Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, Tottori 683-8504, Japan
Tsuyoshi Chijiwa
Central Institute for Experimental Animals, Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210–0821, Japan
Takayuki Isagawa
Data Science Center, Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi 329–0498, Japan
Mariko Tanaka
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113–8654, Japan
Hiroshi Suemizu
Central Institute for Experimental Animals, Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210–0821, Japan
Masato Nakamura
Department of Regenerative Medicine, Tokai University School of Medicine, Shimokasuya, Isehara, Kanagawa 259–1193, Japan
Yohei Miyagi
Research Institute, Kanagawa Cancer Center, Nakao, Asahi-ku, Yokohama 241–8515, Japan
Hiroyuki Aburatani
Division of Genome Sciences, RCAST, The University of Tokyo, Tokyo 113–8654, Japan
Shumpei Ishikawa
Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Experimental Research Buliding, 12thFloor, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8654, Japan; Corresponding author
Summary: The patient-derived xenograft (PDX) model is a versatile tool used to study the tumor microenvironment (TME). However, limited studies have described multi-tumor PDX screening strategies to detect hub regulators during cancer-stroma interaction. Transcriptomes of cancer (human) and stroma (mouse) components of 70 PDX samples comprising 9 distinctive tumor types were analyzed in this study. PDX models recapitulated the original tumors' features, including tumor composition and putative signaling. Particularly, kidney renal clear cell carcinoma (KIRC) stood out, with altered hypoxia-related pathways and a high proportion of endothelial cells in the TME. Furthermore, an integrated analysis conducted to predict paracrine effectors in the KIRC cancer-to-stroma communication detected well-established soluble factors responsible for the hypoxia-related reaction and the so-far unestablished soluble factor, apelin (APLN). Subsequent experiments also supported the potential role of APLN in KIRC tumor progression. Therefore, this paper hereby provides an analytical workflow to find hub regulators in cancer-stroma interactions.
