Department of Molecular and Medical Pharmacology, Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, California.
Division of Hematology/Oncology, Department of Internal Medicine, University of California, Davis, Sacramento, California.
Clin Cancer Res. 2024 Nov 1;30(21):4957-4973. doi: 10.1158/1078-0432.CCR-24-1238.
High-grade complex karyotype sarcomas are a heterogeneous group of tumors with a uniformly poor prognosis. Within complex karyotype sarcomas, there are innumerable genetic changes but identifying those that are clinically relevant has been challenging.
To address this, we utilized a pooled genetic screening approach, informed by The Cancer Genome Atlas (TCGA) data, to identify key drivers and modifiers of sarcoma development that were validated in vivo.
YAP1 and wild-type KRAS were validated as drivers and transformed human mesenchymal stem cells into two distinct sarcoma subtypes, undifferentiated pleomorphic sarcoma and myxofibrosarcoma, respectively. A subset of tumors driven by CDK4 and PIK3CA reflected leiomyosarcoma and osteosarcoma demonstrating the plasticity of this approach and the potential to investigate sarcoma subtype heterogeneity. All generated tumors histologically reflected human sarcomas and had increased aneuploidy as compared to simple karyotype sarcomas. Comparing differential gene expression of TCGA samples to model data identified increased oxidative phosphorylation signaling in YAP1 tumors. Treatment of a panel of soft tissue sarcomas with a combination of YAP1 and oxidative phosphorylation inhibitors led to significantly decreased viability.
Transcriptional co-analysis of TCGA patient samples to YAP1 and KRAS model tumors supports that these sarcoma subtypes lie along a spectrum of disease and adds guidance for further transcriptome-based refinement of sarcoma subtyping. This approach can be used to begin to understand pathways and mechanisms driving human sarcoma development, the relationship between sarcoma subtypes, and to identify and validate new therapeutic vulnerabilities for this aggressive and heterogeneous disease.
高级别复杂核型肉瘤是一组具有均匀不良预后的异质性肿瘤。在复杂核型肉瘤中，存在无数的遗传变化，但确定那些与临床相关的变化一直具有挑战性。
为了解决这个问题，我们利用了一种基于癌症基因组图谱（TCGA）数据的 pooled 遗传筛选方法，以鉴定关键的驱动因子和肉瘤发生的修饰因子，并在体内进行验证。
YAP1 和野生型 KRAS 被验证为驱动因子，将人间质干细胞转化为两种不同的肉瘤亚型，分别为未分化多形性肉瘤和黏液纤维肉瘤。由 CDK4 和 PIK3CA 驱动的一部分肿瘤反映了平滑肌肉瘤和骨肉瘤，这证明了这种方法的可塑性和研究肉瘤亚型异质性的潜力。所有生成的肿瘤在组织学上都反映了人类肉瘤，并且与简单核型肉瘤相比，非整倍体增加。将 TCGA 样本的差异基因表达与模型数据进行比较，确定 YAP1 肿瘤中氧化磷酸化信号增加。用 YAP1 和氧化磷酸化抑制剂的组合治疗一组软组织肉瘤，导致细胞活力显著降低。
对 TCGA 患者样本进行 YAP1 和 KRAS 模型肿瘤的转录共分析支持这些肉瘤亚型处于疾病谱的两端，并为进一步基于转录组的肉瘤亚型细化提供指导。这种方法可用于开始了解驱动人类肉瘤发生的途径和机制、肉瘤亚型之间的关系，并识别和验证这种侵袭性和异质性疾病的新治疗弱点。
