Stem and progenitor cells may divide asymmetrically to self-renew and produce differentiating progeny in a single division. Usually, during an asymmetric cell division (ACD), determinants of self-renewal and differentiation segregate to opposite daughter cells during mitosis and thereby specify distinct cell fates.

Disruption of ACD is seen in many cancers with a stem or progenitor cell component, including malignant gliomas (Sugiarto et al., 2011, Cancer Cell 20:328-40). Yet, it is not clear whether this is a contributing factor or a consequence of neoplastic transformation. Lethal giant larvae 1 (Lgl1), a gene that was initially identified as a tumor suppressor in Drosophila, has been implicated in the asymmetric localization of cell fate determinants in neural progenitor cells (Klezovitch et al., 2004, Genes Dev 18:559-571). Here, we investigated the effects of Lgl1 depletion on distinct hallmarks of glioma.

In murine neural progenitor cells carrying conditional null alleles of Lgl1 (Klezovitch et al., 2004, Genes Dev 18:559-571), depletion of Lgl1 resulted in reduced rates of ACD, increased expression of progenitor markers and impaired differentiation. In an orthotopic model of glioma, driven by expression of EGFRvIII, a frequent and constitutively active mutant form of epidermal growth factor receptor (EGFR), Lgl1 inactivation led to increased tumor invasiveness.

Our data suggest that disruption of ACD in glioma precursor cells promotes maintenance of progenitor features and hampers differentiation. At later stages of gliomagenesis, loss of ACD and cell polarity controls may contribute to tumor invasiveness.

Citation Format: Sandra Gomez-Lopez, Robin G. Lerner, Claudia Petritsch. Lgl1 loss promotes stemness and invasion in EGFRvIII-driven gliomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1942. doi:10.1158/1538-7445.AM2014-1942