Albert Einstein Cancer Center

Glioblastoma multiforme (grade IV glioma) is one of the most aggressive human cancers, with a median survival of less than 1 year. A histopathological hallmark of malignant gliomas is their diffuse infiltration into the surrounding normal brain, which renders surgical extirpation and local radiation ineffective. Currently, there are no anti-invasion therapies available. We have shown that Rac1 and Cdc42, members of the Rho family of small GTPases, play critical roles in glioma invasion in vitro. Therefore, elucidation of the signaling cascades that are mediated by these GTPases should yield novel targets for the discovery of anti-cancer drugs. We currently are dissecting Rho GTPase-mediated signaling pathways that are critical for glioma invasion, both in vitro and in vivo using a number of different approaches.

One project aims to identify the regulators that are critical for Rac and Cdc42 activation in glial tumors. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs). There are 40 RhoGEFs in the human genome that can activate Rac and/or Cdc42 and it is not known which RhoGEFs contribute to the activation of these GTPases in glial tumors. We recently have identified three RhoGEFs, Ect2, Vav3 and Trio, that are overexpressed at the protein level in glioblastoma versus low grade gliomas and have shown that all three GEFs contribute to glioblastoma invasion in vitro. Ongoing research includes siRNA-based screening to identify additional GEFs that regulate glioblastoma cell invasion, examining the activation states of these GEFs glial tumors in situ and identifying how these GEFs are activated. 

 

Selected Recent Publications:

 Chuang Y-Y, Valster A and Symons M. The atypical Rho family GTPase Wrch-1 regulates focal adhesion formation and cell migration. 2007, J Cell Sci., in press. 

  Chan AY, Coniglio SJ, Chuang YY, Michaelson D, Knaus UG, Philips MR and Symons M. Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. 2005, Oncogene. 24, 7821-9. 

Chuang Y, Tran NL, Rusk N, Nakada N, Berens ME and Symons M. Role of synaptojanin 2 in glioma cell migration and invasion. 2004, Cancer Res. 64, 8271-8275.