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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



* FARE Award Winner


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


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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