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

doi:10.1016/j.isci.2024.109247

Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines

iScience. 2024 Feb 16;27(3):109247. doi: 10.1016/j.isci.2024.109247. eCollection 2024 Mar 15.

Authors

Nobuhiko Ogasawara¹, Yoshihito Kano², Yosuke Yoneyama³, Sakurako Kobayashi¹, Satoshi Watanabe¹, Sakura Kirino¹, Fausto D Velez-Bravo⁴, Yourae Hong⁴, Aleksandra Ostapiuk⁴, Pavlo Lutsik⁵, Iichiroh Onishi⁶, Shinichi Yamauchi⁷, Yui Hiraguri¹, Go Ito⁸, Yusuke Kinugasa⁷, Kenichi Ohashi⁹, Mamoru Watanabe⁸, Ryuichi Okamoto¹, Sabine Tejpar⁴, Shiro Yui¹⁰

Affiliations

¹ Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
² Department of Clinical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
³ Institute of Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
⁴ Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
⁵ Computational Cancer Biology and Epigenomics, Department of Oncology, KU Leuven, Leuven, Belgium.
⁶ Department of Diagnostic Pathology, Tokyo Medical and Dental University Hospital, Bunkyo-ku, Tokyo 113-8510, Japan.
⁷ Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
⁸ Advanced Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
⁹ Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
¹⁰ Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.

Abstract

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.

Keywords: Cancer; Classification Description; Stem cell plasticity; Transcriptomics.