Spatial and single-cell colocalisation analysis reveals MDK-mediated immunosuppressive environment with regulatory T cells in colorectal carcinogenesis

Masahiro Hashimoto, Yasuhiro Kojima, Takeharu Sakamoto, Yuki Ozato, Yusuke Nakano, Tadashi Abe, Kiyotaka Hosoda, Hideyuki Saito, Satoshi Higuchi, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Tsuyoshi Hata, Satoshi Nagayama, Koichi Kagawa, Yasuhiro Goto, Mitsuaki Utou, Ayako Gamachi, Kiyomi ImamuraYuta Kuze, Junko Zenkoh, Ayako Suzuki, Kazuki Takahashi, Atsushi Niida, Haruka Hirose, Shuto Hayashi, Jun Koseki, Satoshi Fukuchi, Kazunari Murakami, Tomoharu Yoshizumi, Kenji Kadomatsu, Taro Tobo, Yoshinao Oda, Mamoru Uemura, Hidetoshi Eguchi, Yuichiro Doki, Masaki Mori, Masanobu Oshima, Tatsuhiro Shibata, Yutaka Suzuki, Teppei Shimamura, Koshi Mimori

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Cell–cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. Methods: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell–cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. Findings: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma–carcinoma interface. At early-stage carcinogenesis, cell–cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. Interpretation: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. Funding: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.

Original languageEnglish
Article number105102
JournalEBioMedicine
Volume103
DOIs
Publication statusPublished - May 2024

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Spatial and single-cell colocalisation analysis reveals MDK-mediated immunosuppressive environment with regulatory T cells in colorectal carcinogenesis'. Together they form a unique fingerprint.

Cite this