Dedifferentiation of mature astrocytes by abrogation of Rb tumor suppression leads to Astrocytoma initiation in GEMs

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	CANCER-28

* FARE Award Winner

Authors

• T. Sullivan
• Y. Song
• N. O' Sullivan
• X. Lu
• T. Van Dyke

Abstract

Understanding astrocytoma initiation has been of immense significance. Our lab has developed an adult inducible GEMM for glioblastoma (Grade IV). Inactivation of Rb tumor suppression (TS) by expressing N-terminal 121aa of large T antigen (T121) is sufficient to initiate grade II astrocytoma. Addition of mutant KrasG12D leads to grade III and further PTEN deletion to glioblastomas. Studies from several cancers have identified tumor-initiating cells, a subset of tumor cells with stem cell-like properties responsible for tumorigenesis. We hypothesize that Rb TS inactivation dedifferentiates astrocytes into stem/progenitor-like state generating potential cell(s) of origin for astrocytoma. Immunostaining of progenitor and proliferation markers showed their co-expression in cortex with T121, suggesting a possible dedifferentiation of mature astrocytes. Moreover, astrocyte differentiation marker S100beta was downregulated in T121 cells. Focal induction of T121 in cortex using lenti-cre injection also showed similar results. Furthermore, cortical T121 expressing astrocytes were able to generate neurospheres but astrocytes from wildtype cortex failed to do so. These cells also showed self-renewability, multilineage ability and tumor forming capacity their resemblance to the tumor-initiating cells. With Rb pathway altered in more than 75% of glioblastomas, our results are important in unraveling the tumor initiation process for this deadly disease.

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