iScience
(Mar 2024)
Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines
Nobuhiko Ogasawara,
Yoshihito Kano,
Yosuke Yoneyama,
Sakurako Kobayashi,
Satoshi Watanabe,
Sakura Kirino,
Fausto D. Velez-Bravo,
Yourae Hong,
Aleksandra Ostapiuk,
Pavlo Lutsik,
Iichiroh Onishi,
Shinichi Yamauchi,
Yui Hiraguri,
Go Ito,
Yusuke Kinugasa,
Kenichi Ohashi,
Mamoru Watanabe,
Ryuichi Okamoto,
Sabine Tejpar,
Shiro Yui
Affiliations
Nobuhiko Ogasawara
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Yoshihito Kano
Department of Clinical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Yosuke Yoneyama
Institute of Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Sakurako Kobayashi
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Satoshi Watanabe
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Sakura Kirino
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Fausto D. Velez-Bravo
Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
Yourae Hong
Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
Aleksandra Ostapiuk
Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
Pavlo Lutsik
Computational Cancer Biology and Epigenomics, Department of Oncology, KU Leuven, Leuven, Belgium
Iichiroh Onishi
Department of Diagnostic Pathology, Tokyo Medical and Dental University Hospital, Bunkyo-ku, Tokyo 113-8510, Japan
Shinichi Yamauchi
Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Yui Hiraguri
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Go Ito
Advanced Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Yusuke Kinugasa
Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Kenichi Ohashi
Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Mamoru Watanabe
Advanced Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Ryuichi Okamoto
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
Sabine Tejpar
Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium; Corresponding author
Shiro Yui
Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan; Corresponding author
Journal volume & issue
Vol. 27,
no. 3
Abstract
Read online
Summary: In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.
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