Abstract 1016: Asymmetry-defective oligodendrocyte progenitors are glioma precursors

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Mammalian oligodendrocyte progenitors expressing the chondroitine sulfate proteoglycan NG2 are the largest dividing population in the postnatal, mammalian brain. NG2+ oligodendrocyte progenitors self-renew and generate mature oligodendrocytes. The mechanism by which oligodendrocyte progenitors fulfill their dual function has been unclear. NG2+ oligodendrocyte progenitors are also a cellular origin of oligodendrogliomas, a chemo-sensitive but frequently progressive and lethal type of brain tumor. It is however poorly understood how the normal progenitors turn into tumor cells. We proposed to test whether oligodendrocyte progenitor cells undergo asymmetric cell divisions to generate daughter cells of distinct fate, by asymmetrically segregating cell fate determinants. We further speculated that alterations in asymmetric cell division might predispose cells for or even cause transformation by disrupting the normal balance of self-renewal and differentiation. By analyzing murine oligodendrocyte progenitors in the pair assay, which was developed to visualize asymmetric cell divisions, we discovered that the proteoglycan NG2 segregates asymmetrically, suggestive of asymmetric cell division. By determining the fate of the NG2+ and NG2- daughters, we found that the NG2+ progeny undergoes EGF-dependent self-renewal. In contrast, the NG2- progeny differentiates. By analyzing self-renewal of NG2 deficient oligodendrocyte progenitors from genetically engineered NG2 knock-out mice, we determined that NG2 is required for asymmetric segregation of NG2 and EGF-dependent self-renewal. In a transgenic mouse model for oligodendrogliomas, increased symmetric oligodendrocyte progenitor divisions coincide with abnormal self-renewal rather then differentiation at premalignant stages and leads to neoplastic transformation. Lastly, our analyses of human brain and brain tumor tissue-derived cells showed that asymmetric cell divisions are prevalent in non-neoplastic NG2+ cells and reduced in NG2+ cells from low-grade oligodendrogliomas. Mining of existing brain tumor databases for expression level changes revealed that candidate regulators of asymmetric cell division are frequently mis-expressed in low grade brain oligodendrogliomas. Taken together, we unraveled loss of asymmetric division in premalignant, aberrantly self-renewing differentiation-defective murine oligodendrocyte progenitors and human NG2+ oligodendroglioma cells, thereby explaining initial steps by which oligodendrocyte progenitors transform into oligodendroglioma cells. Our data suggest that asymmetric cell divisions maintain homeostasis in the postnatal oligodendrocyte lineage. In contrast, loss or disruption of asymmetric cell division might be causal to the neoplastic transformation of oligodendrocyte progenitor cells and provide novel points of disruption to which specific glioma therapies can be targeted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1016. doi:1538-7445.AM2012-1016