Comparative analysis of tongue cancer organoids among patients identifies the heritable nature of minimal residual disease

Miwako Sase; Taku Sato; Hajime Sato; Fuyuki Miya; Shicheng Zhang; Hiroshi Haeno; Mihoko Kajita; Tadahide Noguchi; Yoshiyuki Mori; Toshiaki Ohteki

doi:10.1016/j.devcel.2024.10.007

Comparative analysis of tongue cancer organoids among patients identifies the heritable nature of minimal residual disease

Dev Cell. 2024 Nov 2:S1534-5807(24)00607-5. doi: 10.1016/j.devcel.2024.10.007. Online ahead of print.

Authors

Affiliations

¹ Department of Biodefense Research, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo (formerly Medical Research Institute, Tokyo Medical and Dental University [TMDU]), Tokyo 113-8510, Japan; Department of Dentistry, Oral, and Maxillofacial Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
² Department of Biodefense Research, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo (formerly Medical Research Institute, Tokyo Medical and Dental University [TMDU]), Tokyo 113-8510, Japan; Department of Biochemistry and Molecular Biology, Nippon Medical School Graduate School of Medicine, Tokyo 113-8603, Japan.
³ Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Center for Medical Genetics, Keio University School of Medicine, Tokyo 160-8582, Japan.
⁴ Research Institute for Biomedical Science, Tokyo University of Science, Chiba 278-0022, Japan.
⁵ Department of Biodefense Research, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo (formerly Medical Research Institute, Tokyo Medical and Dental University [TMDU]), Tokyo 113-8510, Japan.
⁶ Department of Dentistry, Oral, and Maxillofacial Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
⁷ Department of Biodefense Research, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo (formerly Medical Research Institute, Tokyo Medical and Dental University [TMDU]), Tokyo 113-8510, Japan. Electronic address: ohteki.bre@mri.tmd.ac.jp.

PMID: 39504967
DOI: 10.1016/j.devcel.2024.10.007

Abstract

The relapse of tongue cancer (TC) after chemotherapy is caused by minimal residual disease (MRD), which is a few remaining cancer cells after chemotherapy. To understand the mechanism of MRD in TC, we created a library of TC organoids (TCOs) from 28 untreated TC patients at diverse ages and cancer stages. These TCOs reproduced the primary TC tissues both in vitro and in a xenograft model, and several TCO lines survived after cisplatin treatment (chemo-resistant TCOs). Of note, the chemo-resistant TCOs showed "heritable" embryonic diapause-like features before treatment and activation of the autophagy and cholesterol biosynthetic pathways. Importantly, inhibiting these pathways with specific inhibitors converted the chemo-resistant TCOs into chemo-sensitive TCOs. Conversely, autophagy activation with mTOR inhibitors conferred chemo-resistance on the chemo-sensitive TCOs. This unique model provides insights into the mechanism of MRD formation in TCs, leading to effective therapeutic approaches to reduce the recurrence of TC.

Keywords: autophagy; chemo-resistance; cholesterol biosynthesis; cisplatin; embryonic diapose; minimal residual disease; patient-derived tongue cancer organoids.