Asymmetric cell division drives therapeutic resistance and self-renewal in glioblastoma

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ABSTRACT Therapeutic resistance and tumor recurrence are major barriers to treatment for advanced malignant tumors such as glioblastoma. Glioblastoma is treated with a multimodal approach consisting of surgical resection, radiation, and chemotherapy, yet the overall median survival remains very short (15-18 months). Recent studies identified a specialized self-renewing subpopulation of neoplastic cells, termed cancer stem cells (CSCs), with enhanced tumor initiation capacity that are resistant to many tumor treatment agents. It is therefore postulated that the CSCs surviving anti-cancer therapy give rise to recurrent tumors. To identify new strategies to develop more effective therapies, understanding the mechanisms by which CSCs are maintained is necessary. CSC maintenance is regulated by instructive cues from the microenvironment in which they reside, similarly to untransformed somatic stem cells. The fate of somatic stem cells is regulated by the mode of cell division. An asymmetric cell division maintains a self-renewing stem cell while simultaneously generating one differentiated daughter cell. This mode of division maintains the stem cell reservoir, which is required for regeneration of damaged tissue or for replenishment of cells to maintain tissue homeostasis. Our group and others have demonstrated that CSCs also divide asymmetrically, yet the biological importance of this cell division is not understood. We observed that asymmetric cell division co-enriches multiple growth factor receptors (GFRs) to one of the daughter cells. As these GFRs activate common multiple downstream effectors that are important for CSC maintenance, we hypothesized that the asymmetric inheritance of multiple redundant receptors maintains the self-renewal proficiency of one of the daughter cells at the expense of the other under therapeutic pressure. To test this hypothesis, we established a green fluorescent protein (GFP)-based reporter system that indicates the asymmetric inheritance of GFRs in real time. Using this system, we will investigate: 1) the biological role of asymmetric cell division in CSC maintenance in the presence of therapeutic reagents and 2) the molecular mechanisms through which these co-inherited receptors form redundant signaling networks to support CSC maintenance. Our long-term goal is to understand the consequence of asymmetric cell division in CSCs and to utilize the obtained information to enhance the treatment efficacy of advanced cancers including glioblastoma.