A novel Induced-recurrence PDX model recapitulates epi-genomic features of Glioblastoma recurrence [DNA methylation EPIC]

Glioblastoma remains incurable and, due to its infiltrative growth, high levels of treatment resistance and population of glioma initiating/stem cells (GICs), recurs in all patients. Here we design and characterize a novel induced-recurrence model in which mice xenografted with primary patient-derived GICs are treated with a therapeutic  regimen closely recapitulating patient standard of care, followed by monitoring until tumours recur (IR-PDX). By tracking in vivo tumour growth, we confirm the patient specificity and initial efficacy of treatment prior to recurrence.  Availability of longitudinally matched pairs of primary and recurrent GICs enabled patient-specific evaluation of the faithfulness with which the model recapitulated phenotypes associated with the true recurrence. Through comprehensive multi-omic analyses, we showed that the IR-PDX model recapitulated genomic, epigenetic, and transcriptional state heterogeneity changes upon recurrence in a patient-specific manner. The accuracy of the IR-PDX enabled both novel biological insights, including the positive association between glioblastoma recurrence and levels of ciliated neural stem cell-like tumour cells, and the identification of druggable patient-specific therapeutic vulnerabilities. This proof-of-concept study opens the possibility for prospective precision medicine approaches, in which the IR-PDX model is developed between first diagnosis and disease progression to identify target-drug candidates for use as second line of treatment at recurrence. DNAme of 2 longitudinally-paired primary and recurrent Gliobalstoma tumor samples, alongside patient derived glioma initiating cells (GIC) extracted from human tumors and murine xenograft models seeded with primary or recurrent GICs.

胶质母细胞瘤（Glioblastoma）至今仍属不治之症，因其具有浸润性生长特性、治疗抵抗性极强，且存在胶质瘤起始/干细胞（glioma initiating/stem cells, GICs）亚群，所有患者均会出现肿瘤复发。本研究构建并表征了一种新型诱导复发模型：将患者来源原发性胶质瘤起始/干细胞异种移植至小鼠体内，采用高度贴合患者临床标准治疗的给药方案进行干预，随后持续监测直至肿瘤复发，该模型即为诱导复发型患者来源异种移植模型（induced-recurrence patient-derived xenograft, IR-PDX）。通过追踪体内肿瘤生长情况，我们验证了该模型的患者特异性以及治疗前的初始疗效。纵向匹配的原发性与复发性GICs配对样本的获取，使得我们能够以患者特异性的方式，评估该模型对真实复发相关表型的重现忠实程度。通过全面的多组学分析，我们证实IR-PDX模型能够以患者特异性方式重现复发过程中基因组、表观基因组及转录组状态的异质性变化。该模型的准确性不仅助力了多项全新生物学发现，例如胶质母细胞瘤复发与纤毛神经干细胞样肿瘤细胞水平呈正相关，还帮助识别了具有临床可靶向性的患者特异性治疗脆弱靶点。这项概念验证研究为前瞻性精准医学策略提供了可行方向：即在首次诊断至疾病进展期间构建IR-PDX模型，以筛选可在肿瘤复发时作为二线治疗方案的靶标药物。本数据集包含2对纵向匹配的原发性与复发性胶质母细胞瘤样本的DNA甲基化组（DNAme）数据，以及从人类肿瘤中提取的、或接种了原发性/复发性GICs的小鼠异种移植模型中获得的患者来源GICs的相关组学数据。