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Abstract CN07-01: Understanding the role of stem-like tumor cells in proneural glioma

The ID (Inhibitor of DNA-binding) gene family regulates self-renewal in adult neural stem cells. Cells expressing high levels of Id1 in the neurogenic niches of the adult brain define the B1 stem cell populations and Id proteins are essential for self-renewal and the maintenance of multipotency. A decline in Id1 levels is associated with the progression to a progenitor-like cell type in which the bHLH marker Olig2 becomes highly expressed. Since the discovery of stem-like and progenitor-like cell populations within high-grade gliomas, there has been a great deal of interest in elucidating their contributions to tumorigenesis. However, analyses are complicated by the lack of reliable marker sets to definitively isolate and characterize these distinct cell lineages. Using a genetically relevant mouse model of high-grade proneural glioma, we show that high Id1 expression (Id1high) identifies self-renewing, multipotent tumor cells, while low Id1 expression (Id1low) identifies progenitor-like cells characterized by Olig2 expression and limited self-renewal capacity, thus recapitulating what is observed in the normal neurogenic niche. Id1high cells generate tumors upon orthotopic transplantation, but surprisingly, Id1low cells do so with shorter latency and higher penetrance, despite their limited self-renewal capacity. Both Id1high and Id1low cells generate tumors with high-grade features and histopathology similar to the parental tumors. Purified Id1high cells give rise to Id1low cells during tumor formation thereby possibly fueling the generation of the more tumorigenic progenitor-like population. Targeting the more progenitor-like cells via knockdown of Olig2 results in a dramatic survival benefit. These data highlight an important distinction between self-renewal capacity and tumor initiation potential, underscoring the importance of non-stem cell lineages in brain tumor disease progression. Citation Format: Lindy Elise Barrett, Hyung-song Nam, Robert Benezra. Understanding the role of stem-like tumor cells in proneural glioma. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN07-01.