Sase Miwako, Sato Taku, Sato Hajime, Miya Fuyuki, Zhang Shicheng, Haeno Hiroshi, Kajita Mihoko, Noguchi Tadahide, Mori Yoshiyuki, Ohteki Toshiaki
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.
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.
Dev Cell. 2025 Feb 3;60(3):396-413.e6. doi: 10.1016/j.devcel.2024.10.007. Epub 2024 Nov 5.
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.
化疗后舌癌（TC）复发是由微小残留病（MRD）引起的，MRD是化疗后残留的少数癌细胞。为了解TC中MRD的机制，我们从28名不同年龄和癌症阶段的未经治疗的TC患者中创建了一个TC类器官（TCO）库。这些TCO在体外和异种移植模型中都再现了原发性TC组织，并且几个TCO系在顺铂治疗后存活（化疗耐药TCO）。值得注意的是，化疗耐药TCO在治疗前表现出“可遗传”的胚胎滞育样特征，并激活了自噬和胆固醇生物合成途径。重要的是，用特异性抑制剂抑制这些途径可将化疗耐药TCO转化为化疗敏感TCO。相反，用mTOR抑制剂激活自噬可赋予化疗敏感TCO化疗抗性。这个独特的模型为TC中MRD形成的机制提供了见解，从而产生了减少TC复发的有效治疗方法。
