一份仓促的、可移植的儿童高级胶质母细胞瘤模型汇编揭示了亚型特异性的治疗易感性。
A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities.
发表日期：2023 Apr 03
作者：
Michael McNicholas, Antonella De Cola, Zahedeh Bashardanesh, Amelia Foss, Cameron B Lloyd, Steven Hebert, Damien Faury, Augusto Faria Andrade, Nada Jabado, Claudia L Kleinman, Manav Pathania
来源：
Brain Structure & Function
摘要：
小儿高级别胶质母细胞瘤（pHGGs）是致命的、不可治愈的脑肿瘤，通常由组蛋白基因的克隆性突变驱动。它们通常带有一系列额外的基因突变，与不同的年龄、解剖位置和肿瘤亚型相关。我们开发了代表16种不同子型的模型，由特定脑区靶向不同组合的突变驱动。肿瘤产生的延迟时间不同，从这些模型中获得的细胞系在具有高穿透力的同种异体免疫小鼠中移植成功。针对性药物筛选发现了意外的选择性易感性：H3.3G34R / PDGFRAC235Y易感于FGFR抑制，H3.3K27M / PDGFRAWT易感于PDGFRA抑制，H3.3K27M / PDGFRAWT和H3.3K27M / PPM1DC / PIK3CAE545K易感于MEK和PIK3CA的联合抑制。此外，带有PIK3CA、NF1和FGFR1突变的H3.3K27M肿瘤更具侵袭性，带有不同的额外表型，如外生性扩散、颅神经浸润和脊柱转移。总的来说，这些模型揭示了不同的伴侣突变对pHGG细胞组成、延迟、侵袭性和治疗敏感性产生不同的影响。
Pediatric high-grade gliomas (pHGGs) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomical locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities- H3.3G34R/PDGFRAC235Y to FGFR inhibition, H3.3K27M/PDGFRAWT to PDGFRA inhibition, and H3.3K27M/PDGFRAWT and H3.3K27M/PPM1DC/PIK3CAE545K to combined inhibition of MEK and PIK3CA. Moreover, H3.3K27M tumors with PIK3CA, NF1 and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity.