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

doi:10.1016/j.isci.2021.103322

Multi-tumor analysis of cancer-stroma interactomes of patient-derived xenografts unveils the unique homeostatic process in renal cell carcinomas

iScience. 2021 Oct 21;24(11):103322. doi: 10.1016/j.isci.2021.103322. eCollection 2021 Nov 19.

Authors

Kuniyo Sueyoshi^{1

2}, Daisuke Komura¹, Hiroto Katoh¹, Asami Yamamoto¹, Takumi Onoyama^{1

3}, Tsuyoshi Chijiwa⁴, Takayuki Isagawa⁵, Mariko Tanaka⁶, Hiroshi Suemizu⁴, Masato Nakamura⁷, Yohei Miyagi⁸, Hiroyuki Aburatani⁹, Shumpei Ishikawa¹

Affiliations

¹ Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Experimental Research Buliding, 12Floor, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8654, Japan.
² Department of Thoracic Surgery, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
³ Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, Tottori 683-8504, Japan.
⁴ Central Institute for Experimental Animals, Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan.
⁵ Data Science Center, Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
⁶ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan.
⁷ Department of Regenerative Medicine, Tokai University School of Medicine, Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
⁸ Research Institute, Kanagawa Cancer Center, Nakao, Asahi-ku, Yokohama 241-8515, Japan.
⁹ Division of Genome Sciences, RCAST, The University of Tokyo, Tokyo 113-8654, Japan.

Abstract

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.

Keywords: Cancer; Cancer systems biology.