Abstract 149: Tumor suppression by regulator of asymmetric cell division in glioma

We previously discovered that oligodendrocyte progenitor cells (OPC) undergo asymmetric cell division and symmetric, self-renewing divisions at an equal rate, whereby they may establish homeostasis. The proteoglycan and OPC marker NG2 plays a critical role in establishing asymmetric cell division (1). Studies in genetically engineered mouse models identified OPC as a putative cellular origin of human glioma (2,3). Studies also showed that premalignant OPC (aka glioma precursor) increase rates of symmetric, self-renewing divisions at the expense of asymmetric division, suggesting that tipping the balance towards symmetric divisions might disrupt homeostasis and lead to cancer. The objective of this project is to gain functional insights into asymmetric division to assess its role in maintaining tissue homeostasis and tumor suppression. Using our novel FACS-based approach we were able to identify that several conserved regulators of asymmetric division, including the WD40 protein Lethal giant larvae1 (Lgl1) protein, are upregulated in asymmetric versus symmetric dividing OPC. We genetically enforced deletion of Lgl1 in OPC conditionally by injecting tamoxifen into triple transgenic mice obtained by breeding Lgl1fl/fl NG2CreERT2 and red fluorescence Cre reporter mice. Cre-conditional deleted Lgl1 OPC were analyzed for changes in cell division mode, proliferation rate and differentiation in vivo and ex vivo. Whole-transcriptome analyses of Lgl1-deleted OPC followed by Ingenuity Pathway Analyses revealed significant changes in several pathways, including in receptor-mediated endocytosis. Functional analyses were conducted to test if Lgl1 regulates endocytosis in OPC. Our results show that Lgl1 deletion cooperates with CDKN2A homozygous deletion to form glioma from OPC, albeit with long latency. Lgl1-deleted OPC show increased rates of symmetric, self-renewing division and proliferative rate at the expense of asymmetric divisions and differentiation. Lgl1 regulates endocytosis of NG2 and by routing NG2 complex to the lysosome for degradation, Lgl1 may establish the asymmetric NG2 distribution, which is critical for asymmetric division. Taken together, our data identified a conserved regulator of asymmetric OPC division and showed that loss of such a regulator not only disrupts asymmetric divisions but also leads to premalignant changes and neoplastic transformation and the accumulation of glioma precursor. Investigations into the mechanistic details of asymmetric division and the potential role for endocytosis in cell fate determination of OPC and gliomagenesis are ongoing. References: 1. Sugiarto et al., Cancer Cell 2011;20:328. 2. Persson et al., Cancer Cell 2010:18:229. 3. Liu et al., Cell 2011:146:209. Citation Format: Mathieu Daynac, Malek Chouchane, Alex Valenzuela, Claudia K. Petritsch. Tumor suppression by regulator of asymmetric cell division in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 149.