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Glioblastoma as a disease of asymmetric cell division

Ian AJ Lorimer, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, K1H 8L6, Canada

The lethal giant larvae mutant is a well-known model of brain cancer in Drosophila. Detailed studies have shown that the neoplastic overgrowth of brain tissue in this model is due to preferential expansion of neural stem cells. In wild type Drosophila, neural stem cells divide asymmetrically to give rise to a daughter neural stem cell and a second daughter cell that undergoes differentiation into neurons or glial cells. Expansion of the neural stem cells in lethal giant larvae mutants is a consequence of these cells preferentially undergoing symmetric cell division to give rise to two daughter neural stem cells. Although the Drosophila lethal giant larvae mutant was described over forty years ago, its relevance to human glioblastoma had not been assessed until recently. We investigated the function of Lgl1, a human homolog of the Drosophila lethal giant larvae gene, in primary glioblastoma cultures from patients. These primary glioblastoma cultures have stem cell like properties in that they uniformly express nestin and sox2, and can be induced to differentiate along neuronal and astrocytic lineages. We have shown that Lgl1is constitutively inactivated by phosphorylation in these cells. Restoration of Lgl1 function in primary glioblastoma cultures resulted in their differentiation along the neuronal lineage in vitro and in vivo, indicative of a shift from symmetric to asymmetric cell division. In addition, restoration of Lgl1 function reduced the invasive properties of primary glioblastoma cells both in vitro and in vivo. Lgl1 inactivation therefore has similar consequences in Drosophila brain cancer and human glioblastoma, promoting both symmetric cell division and invasive behaviour.

Format: Oral communication

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