PO.MCB01.01 · 分子与细胞生物学
染色体外DNA（ecDNA）介导的复制应激作为高危髓母细胞瘤中潜在可靶向的弱点
Extrachromosomal DNA (ecDNA)-mediated replication stress as a potential targetable vulnerability in high-risk medulloblastoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
染色体外DNA（ecDNA）扩增是癌症演化和进展的关键驱动因素。在髓母细胞瘤中，ecDNA存在于约18%的病例中，并与患者生存不良相关。然而，其在髓母细胞瘤患者的肿瘤进展和治疗耐药中的作用仍知之甚少。本研究探讨ecDNA介导的复制应激（RS）作为高危髓母细胞瘤中潜在可靶向的弱点，重点关注携带MYC扩增的肿瘤。利用来自儿童脑肿瘤图谱（Pediatric Brain Tumor Atlas）186例患者队列的RNA测序数据，我们进行了基因集富集分析（GSEA），发现与无扩增的髓母细胞瘤相比，有扩增的髓母细胞瘤中RS显著富集。随后，我们研究了使用BBI-2779（Boundless Bio公司开发的一种新型、选择性、强效抑制剂）对检查点激酶1（CHK1）进行药理学抑制在MYC ecDNA阳性（D425和D458）和MYC-HSR（D283）髓母细胞瘤细胞系中的作用。我们的结果显示，ecDNA阳性细胞系相较于MYC-HSR细胞对CHK1抑制表现出更高的敏感性和更强的剂量依赖性反应。接下来，我们将使用从Rady Children's Hospital-San Diego采集的肿瘤活检样本生成的患者来源异种移植（PDX），连同细胞系模型，监测CHK1抑制后的肿瘤反应和ecDNA拷贝数动态。随后，我们将进行多组学单细胞测序，以鉴定治疗诱导出现的新型ecDNA变异体。
关键词：髓母细胞瘤，染色体外DNA，ecDNA，基因组不稳定性，治疗耐药，肿瘤异质性
查看英文原文 English abstract
Extrachromosomal DNA (ecDNA) amplification is a key driver of cancer evolution and progression. In medulloblastoma, ecDNA is present in approximately 18% of cases and is associated with poor patient survival. However, its role in tumor progression and treatment resistance for patients with medulloblastoma remains poorly understood. This study investigates ecDNA-mediated replication stress (RS) as a potentially targetable vulnerability in high-risk medulloblastoma with a focus on tumors harboring MYC amplifications. Using RNA sequencing data from a cohort of 186 patients from the Pediatric Brain Tumor Atlas, we performed gene set enrichment analysis (GSEA) and found RS to be significantly enriched in medulloblastomas with amplifications compared to those without amplifications. We then investigate the effects of pharmacological checkpoint kinase 1 (CHK1) inhibition using BBI-2779-a novel, selective, and potent inhibitor developed by Boundless Bio-on MYC ecDNA-positive (D425 and D458) and MYC-HSR (D283) medulloblastoma cell lines. Our results show that ecDNA-positive lines exhibit greater sensitivity and a stronger dose-dependent response to CHK1 inhibition than MYC-HSR cells. Moving forward, we will use patient-derived xenografts (PDXs) generated from tumor biopsies collected at Rady Children's Hospital-San Diego, along with cell line models, to monitor tumor response and ecDNA copy number dynamics following CHK1 inhibition. We will then perform multiome single-cell sequencing to identify therapy-induced emergence of novel ecDNA variants.
Keywords: Medulloblastoma, Extrachromosomal DNA, ecDNA, genomic instability, therapy resistance, tumor heterogeneity
利益披露 Disclosure
J. Wang,
Odyssey Therapeutics Inc Employment.
Y. Lo, None..
E. Adeyan, None.