高级别浆液性卵巢癌同基因小鼠模型的比较分析。
Comparative analysis of syngeneic mouse models of high-grade serous ovarian cancer.
发表日期:2023 Nov 13
作者:
David P Cook, Kristianne J C Galpin, Galaxia M Rodriguez, Noor Shakfa, Juliette Wilson-Sanchez, Maryam Echaibi, Madison Pereira, Kathy Matuszewska, Jacob Haagsma, Humaira Murshed, Alison O Cudmore, Elizabeth MacDonald, Alicia Tone, Trevor G Shepherd, James J Petrik, Madhuri Koti, Barbara C Vanderhyden
来源:
Cellular & Molecular Immunology
摘要:
卵巢癌复发率高且治疗反应差。重现人类疾病的临床前模型对于开发新的治疗方法至关重要。同基因小鼠模型允许产生包含所有非恶性细胞类型的肿瘤,但数量有所增加,细胞来源类型、转化方法以及最终产生的肿瘤的特性各不相同。在此,我们基于 22 个细胞系模型以及 12 个细胞系模型的囊内和腹膜内肿瘤的转录组学分析,对高级别浆液性卵巢癌模型进行了比较分析。在细胞系中,我们发现了不同的信号传导活性,例如 STOSE 中炎症信号传导的升高和 OVE16 型号,以及 ID8 和 OVE4 型号中的 MAPK/ERK 信号;代谢差异,例如几个工程 ID8 亚克隆中糖酵解相关表达的减少;以及相关的功能特性,包括 EMT 激活、PD-L1 和 MHC I 类表达的差异以及预测的化疗敏感性。在肿瘤样本中,我们观察到法氏囊内肿瘤的变异性和基质含量增加。最后,我们预测了用临床相关突变设计的 ID8 模型的微环境差异。我们预计这项工作将成为一种宝贵的资源,提供新的见解来帮助选择特定实验目标的模型。© 2023。作者。
Ovarian cancers exhibit high rates of recurrence and poor treatment response. Preclinical models that recapitulate human disease are critical to develop new therapeutic approaches. Syngeneic mouse models allow for the generation of tumours comprising the full repertoire of non-malignant cell types but have expanded in number, varying in the cell type of origin, method for transformation, and ultimately, the properties of the tumours they produce. Here we have performed a comparative analysis of high-grade serous ovarian cancer models based on transcriptomic profiling of 22 cell line models, and intrabursal and intraperitoneal tumours from 12. Among cell lines, we identify distinct signalling activity, such as elevated inflammatory signalling in STOSE and OVE16 models, and MAPK/ERK signalling in ID8 and OVE4 models; metabolic differences, such as reduced glycolysis-associated expression in several engineered ID8 subclones; and relevant functional properties, including differences in EMT activation, PD-L1 and MHC class I expression, and predicted chemosensitivity. Among tumour samples, we observe increased variability and stromal content among intrabursal tumours. Finally, we predict differences in the microenvironment of ID8 models engineered with clinically relevant mutations. We anticipate that this work will serve as a valuable resource, providing new insight to help select models for specific experimental objectives.© 2023. The Author(s).