Abstract
Despite aggressive standard and novel targeted therapies, malignant gliomas recur invariably and develop therapy resistance. Our previous studies have shown that oligodendrocyte progenitor cells (OPCs) undergo asymmetric cell division whereby they generate self-renewing and differentiating cells in a single division by unequally segregating cell fate determinants. We found that premalignant OPC, the origin of glioma in genetically engineered mouse models, exhibit disrupted asymmetric divisions, together with other hallmarks of cancer, including hyper-proliferation (Sugiarto et al., 2011, Cancer Cell 20:328-40). Yet, it is not clear whether disruption of asymmetric division of OPCs 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). We investigated the effects of Lgl1 depletion on distinct hallmarks of glioma. We find that in murine OPC carrying conditional null alleles of Lgl1, depletion of Lgl1 resulted in reduced rates of asymmetric cell division and other defects previously associated with glioma precursors. Our data suggest that loss of asymmetric divisions contribute to neoplastic transformation. Asymmetric cell divisions of stem and progenitor cells are a point of disruption to which novel therapies can be targeted. Underlying mechanisms for the phenotypes of Lgl1 knockout and their relevance for malignant glioma will be discussed.
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