Abstract
Background:
Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in adults. Characterization of GBM heterogeneity has identified four molecular subtypes based on transcriptomic profile: classical, neural, proneural and mesenchymal. Tumors harboring the mesenchymal gene signature are considered the most aggressive, invasive, and multitherapy-resistant. We identify the polyamine acetylation enzyme, SAT1 (spermidine/spermine N1-acetyltransferase 1) as a component of the mesenchymal gene signature and mesenchymal-associated gene sets including (1) Hallmark EMT and (2) Hallmark TNFa signaling via NF-κB.
Design/Methods:
To validate the role of SAT1 in driving mesenchymal features in vivo, we utilized a genetically flexible, CRISPR-based model of GBM. Tumor bearing mice were generated through in utero electroporation, resulting in ablation of PTEN, P53 and NF1 in developing cortical cells. SAT1 knockout was achieved through cloning of additional guide RNA’s against SAT1 into the tumor initiating plasmid.
Results:
In our model, we found increased levels of both SAT1 and acetylated polyamines in tumors compared to normal brain. Ablation of SAT1 was insufficient to prolong overall survival in mice but rendered the otherwise treatment resistant tumors highly sensitive to chemoRT. Bulk RNA sequencing of murine tumors revealed that SAT1 knockout resulted in reduced expression of the mesenchymal gene signature as well as genes implicated in EMT and TNFa/NFKb signaling.
Conclusions:
Collectively, these results reveal that SAT1 not only identifies mesenchymal GBM but also drives expression of the mesenchymal gene signature and mesenchymal features including multi-therapy resistance.
Citation Format: Ayush B. Rana, Timothy M. Horton, Vijay S. Thakur, Scott M. Welford. The polyamine acetylation enzyme SAT1 drives mesenchymal features and therapeutic resistance in glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3674.