建立和验证SMARCA4失活和ARID1A/ARID1B共失活的分化不良子宫内膜癌的临床前模型。
Establishment and validation of preclinical models of SMARCA4-inactivated and ARID1A/ARID1B co-inactivated dedifferentiated endometrial carcinoma.
发表日期：2023 Aug 07
作者：
Nelson K Y Wong, Marta Llaurado Fernandez, Felix K F Kommoss, Pooja Praveen Kumar, Hannah Kim, Jiahui Liu, Guihua Zhang, Mackenzie Coatham, Yen-Yi Lin, Anne M Haegert, Stanislav Volik, Stephane Le Bihan, Colin C Collins, Yangxin Fu, Lynne M Postovit, Andreas von Deimling, Rebecca Wu, Hui Xue, Yuzhuo Wang, Martin Köbel, Mark S Carey, Cheng-Han Lee
来源：
GYNECOLOGIC ONCOLOGY
摘要：
脱分化子宫内膜癌（DDEC）是一种罕见且临床高度侵袭性的子宫内膜癌亚型，其特点是SWItch/Sucrose Non-Fermentable（SWI/SNF）复合物蛋白的基因失活。它对传统系统治疗的反应不佳，其快速进展的临床过程限制了试验额外治疗的疗效窗口。这凸显了对生物学准确的临床前肿瘤模型的迫切需求，以加速治疗的发展。手术样本中提取DDEC肿瘤并植入免疫功能受损的小鼠中，用于构建患者源性异种移植模型（PDX）和细胞系。对患者肿瘤和建立的PDX模型进行了组织学、免疫表型、遗传和表观遗传特征的表征。评估了SMARCA4缺陷DDEC模型对之前报告的KDM6A/B抑制剂（GSK-J4）的敏感性，该抑制剂被证明对其他SMARCA4缺陷癌症类型有疗效。三个DDEC模型在体外和体内均表现出快速生长，其中两个PDX模型在体内自发发展转移。PDX肿瘤保持相同的未分化组织学和免疫表型，显示了与相应亲本肿瘤相同的基因组和甲基化特征，包括一例缺乏错配修复（MMR）功能、基因组中SMARCA4失活的DDEC，以及两例缺乏MMR功能、基因组中ARID1A和ARID1B均失活的DDEC。虽然SMARCA4缺陷的细胞系对GSK-J4显示出低微级的敏感性，但对应的PDX模型并未观察到显著的肿瘤生长抑制。这些建立的患者肿瘤来源模型准确地描绘了DDEC，并代表了获得对这种侵袭性肿瘤的治疗见解的有价值的临床前工具。版权所有 © 2023 Elsevier Inc. 保留所有权利。
Dedifferentiated endometrial cancer (DDEC) is an uncommon and clinically highly aggressive subtype of endometrial cancer characterized by genomic inactivation of SWItch/Sucrose Non-Fermentable (SWI/SNF) complex protein. It responds poorly to conventional systemic treatment and its rapidly progressive clinical course limits the therapeutic windows to trial additional lines of therapies. This underscores a pressing need for biologically accurate preclinical tumor models to accelerate therapeutic development.DDEC tumor from surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and cell line development. The histologic, immunophenotypic, genetic and epigenetic features of the patient tumors and the established PDX models were characterized. The SMARCA4-deficienct DDEC model was evaluated for its sensitivity toward a KDM6A/B inhibitor (GSK-J4) that was previously reported to be effective therapy for other SMARCA4-deficient cancer types.All three DDEC models exhibited rapid growth in vitro and in vivo, with two PDX models showing spontaneous development of metastases in vivo. The PDX tumors maintained the same undifferentiated histology and immunophenotype, and exhibited identical genomic and methylation profiles as seen in the respective parental tumors, including a mismatch repair (MMR)-deficient DDEC with genomic inactivation of SMARCA4, and two MMR-deficient DDECs with genomic inactivation of both ARID1A and ARID1B. Although the SMARCA4-deficient cell line showed low micromolecular sensitivity to GSK-J4, no significant tumor growth inhibition was observed in the corresponding PDX model.These established patient tumor-derived models accurately depict DDEC and represent valuable preclinical tools to gain therapeutic insights into this aggressive tumor type.Copyright © 2023 Elsevier Inc. All rights reserved.