Interactions Between Ploidy and Resource Availability Shape Clonal Evolution in Glioblastoma

倍性 生物信息学 生物 胶质母细胞瘤 脑瘤 肿瘤微环境 恶性肿瘤 肿瘤进展 癌症研究 细胞 病理 癌症 医学 肿瘤细胞 遗传学 基因
作者
Zuzanna Nowicka,Frederika Rentzeperis,Vural Tagal,Jamie K. Teer,Didem Ilter,Richard J. Beck,Jackson P. Cole,Ana Forero Pinto,Joanne D. Tejero,Elisa Scanu,Thomas Veith,William Dominguez‐Viqueira,Konstantin Maksin,Francisco Carrillo‐Pérez,Olivier Gevaert,Xiaonan Xu,Florian A. Karreth,Mahmoud A. Abdalah,Giada Fiandaca,S. Pasetto
出处
期刊:Cancer Research [American Association for Cancer Research]
标识
DOI:10.1158/0008-5472.can-24-0401
摘要

Abstract Glioblastoma (GBM) is the most aggressive form of primary brain tumor. The infiltrative nature of GBM makes complete surgical resection impossible. The selective forces that govern gliomagenesis are strong, shaping the composition of tumor cells during the initial progression to malignancy with late consequences for invasiveness and therapy response. Here, we developed a mathematical model that incorporates ploidy level and the nature of the brain tissue microenvironment to simulate the growth and invasion of GBM and used the model to make inferences about GBM initiation and response to standard-of-care treatment. The spatial distribution of resource access in the brain was approximated through integration of in silico modeling, multi-omics data, and image analysis of primary and recurrent GBM. The in silico results suggested that high ploidy cells transition faster from oxidative phosphorylation to glycolysis than low ploidy cells because they are more sensitive to hypoxia. Between surgeries, simulated tumors with different ploidy compositions progressed at different rates; however, whether higher ploidy predicted fast recurrence was a function of the brain microenvironment. Historical data supported the dependence on available resources in the brain, as shown by a significant correlation between the median oxygen levels in human tissues and the median ploidy of cancers that arise in the respective tissues. Taken together, these findings suggest that availability of metabolic substrates in the brain drives different cell fate decisions for cells with different ploidy, thereby modulating both gliomagenesis and GBM recurrence.
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