A switch from asymmetric to symmetric division causes the formation of glioma, a brain tumor, which frequently progress and leads to the patient's death. This study addresses an important aspect of human health, which is to characterize the Aspm protein as a master regulator of symmetric cell divisions and gliomagenesis and to investigate Aspm-regulated functions as therapeutic opportunities. The proposed research is a paradigm for determining the regulation of cell divisions in all cancers and is relevant to the NIH's mission in its have far- reaching therapeutic impact.
Novel therapeutic approaches are desperately needed to improve the prognosis for glioma patients. Developing such approaches will require the delineation of key regulatory networks specific to glioma cells and leading to neoplastic transformation and enabling tumor growth. Past studies in mouse models identified oligodendrocyte progenitor cells (OPC) as putative cellular origin of astrocytoma and oligodendroglioma. Data from our lab showed that the switch from asymmetric, self-sustaining to symmetric, self-renewing divisions is a critical step in the neoplastic transformation of OPC. Therapies specifically interfering with aberrant symmetric cell divisions are expected to eliminate malignant OPCs and disrupt tumor growth. It is our long-term goal to develop such therapies, by defining the effect of glioma- associated genetic alterations on the asymmetric-to-symmetric cell division mode switch. The objective of this proposal is to test the hypothesis that abnormal spindle microcephaly associated Aspm mRNA expression is upregulated in glioma cells by constitutive-active receptor tyrosine kinase signaling via PI3K- AKT. We further propose that Aspm protein positively regulates symmetric divisions and thereby promotes neoplastic transformation and malignant growth. Functionally, Aspm positively regulates mitotic spindle integrity and positioning. We will achieve our objective by pursuing two independent aims. In Aim 1, we propose to identify the molecular switch from asymmetric to symmetric division in OPC, by determining if activation of the PDGFRα/EGFR-PI3K-AKT axis directly elevates Aspm transcript levels and thereby positively regulates symmetric cell division mode and increases proliferation rate. We expect that upon completion of these experiments, we will for the first time have demonstrated that the switch of cell division mode is regulated by an extrinsic signal through modulation of Aspm levels. In Aim 2. we will validate Aspm as a proto-oncogene and Aspm functions as therapeutic opportunities. We will suppress Aspm expression using RNAi in a selected panel of glioma cells with constitutively active PDGFRα or EGFR signaling. We anticipate that Aspm suppression will cause glioma cells to favor asymmetric divisions, which will decrease their proliferation rate and reduce their malignant potential. We anticipate that Aspm spindle regulatory functions provide novel therapeutic vulnerabilities in glioma cells. These studies can delineate a paradigm for enforcing symmetric cell division and tumorigenesis in all progenitor-driven tumors. By unraveling Aspm upregulation as a specific step in the neoplastic transformation of progenitor cells we identify a point of susceptibility for cancer therapies and provide a treatment paradigm for other progenitor-derived cancers.