Abstract 4942: Deletion of the asymmetry regulator Lgl1 contributes to tumor stemness and invasiveness.

Abstract

Abstract In the developing and adult brain asymmetric cell division (ACD) maintains a balance between self-renewing and differentiated progeny of neural stem and progenitor cells. The WD protein lethal giant larvae 1 (Lgl1) regulates the distribution of polarity proteins in dividing cells and thereby establishes an axis of polarity, which is crucial for proper asymmetric divisions to occur (Baek et al. Mutat Res. 1999; 436; 131-6). Lgl, along with other asymmetry regulators, have been identified as a putative tumor suppressor gene in Drosophila. There remains debate as to whether disrupting ACD by itself is sufficient to cause tumor initiation by mammalian stem and progenitor cells. We have previously shown that expression of multiple asymmetry regulators is disrupted in human glioma (Sugiarto et al. Cancer Cell; 2011; 20; 320-340). Here we address our hypothesis that ACD defects are crucial for tumorigenesis, by delineating the role of Lgl1 in tumor initiation and progression. Using mouse neural stem cells (NSCs) isolated from genetically modified Lgl1lox/lox mice (Klezovitch et al. Genes Dev. 2004; 18; 559-71) we investigated the contribution of Lgl1 to various hallmarks of cancer in vitro and in vivo. We demonstrate that loss of Lgl1 in mouse NSC and oligodendrocyte precursor cells disrupts ACD and increases the expression of early-stage precursor cell markers. Deletion of Lgl1 does not increase proliferation in vitro and deletion of Lgl1 alone does not transform cells transplanted into immunocompromised mice. However properties associated with a high-grade tumor, including invasiveness and stem cell marker expression, are increased when Lgl1 is deleted in the context of oncogenic EgfrVIII expression. Increase in tumor invasiveness has previously been demonstrated to be associated with an increase in stem cell marker expression (Molina et al. Neoplasia. 2010; 12; 453-63). Our data suggest that loss of asymmetry in tumor precursor cells blocks differentiation and contributes to tumor progression by increasing stemness and hence invasiveness. Citation Format: Robin G. Lerner, Loan Nguyen, Claudia Petritsch. Deletion of the asymmetry regulator Lgl1 contributes to tumor stemness and invasiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4942. doi:10.1158/1538-7445.AM2013-4942