Nakagawa Shunsaku, Sato Taku, Ohashi Eriko, Kajita Mihoko, Miya Fuyuki, Yamamoto Kouhei, Yotsumata Hiroki, Yamaguchi Kazuya, Nakajima Yasuaki, Miura Akinori, Kinugasa Yusuke, 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, Japan.
Department of Gastrointestinal Surgery, Institute of Science Tokyo, Tokyo, Japan.
Commun Biol. 2025 Apr 1;8(1):507. doi: 10.1038/s42003-025-07869-4.
Esophageal squamous cell carcinoma (ESCC) is a deadly cancer with a poor prognosis and a high recurrence rate after chemotherapy, posing a significant clinical challenge. To elucidate the molecular basis of chemotherapy (chemo)-resistance and to develop methods to effectively eliminate chemo-resistant tumor clones, we established an ESCC organoid (ESCCO) library from 24 ESCC patients of various stages, ages, and treatments. These ESCCOs faithfully recapitulate the oncogenic mutations observed in the original ESCC tissues and manifest tumorigenic properties when xenografted. The ESCCOs respond differently to cisplatin and 5-fluorouracil, chemotherapeutic agents commonly used to treat ESCC patients, with 7 ESCCOs exhibiting potent chemo-resistance. Notably, the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs. These genes can serve as valuable biomarkers to stratify chemo-resistant ESCCs in histopathological specimens. Through drug screening using the ESCCO library, we reveal that fedratinib effectively induces cell death in chemo-resistant ESCCOs. Collectively, our human ESCCO model offers novel insights into the mechanism of chemo-resistance in ESCCs, which is critical for developing effective therapeutic approaches to eradicate the recurrence of ESCCs.
食管鳞状细胞癌（ESCC）是一种致命的癌症，预后较差，化疗后复发率高，构成了重大的临床挑战。为了阐明化疗耐药的分子基础并开发有效消除化疗耐药肿瘤克隆的方法，我们从24名不同阶段、年龄和治疗情况的ESCC患者中建立了一个ESCC类器官（ESCCO）库。这些ESCCOs忠实地再现了原始ESCC组织中观察到的致癌突变，并在异种移植时表现出致瘤特性。ESCCOs对顺铂和5-氟尿嘧啶（常用于治疗ESCC患者的化疗药物）的反应不同，其中7个ESCCOs表现出强大的化疗耐药性。值得注意的是，与敏感的ESCCOs相比，化疗耐药的ESCCOs在抗氧化应激反应途径中涉及的基因更高，并且其基因座处的染色质更易接近。这些基因可作为有价值的生物标志物，用于在组织病理学标本中对化疗耐药的ESCCs进行分层。通过使用ESCCO库进行药物筛选，我们发现fedratinib能有效诱导化疗耐药的ESCCOs细胞死亡。总的来说，我们的人类ESCCO模型为ESCCs化疗耐药机制提供了新的见解，这对于开发有效的治疗方法以根除ESCCs的复发至关重要。
