Glioblastomas (GBMs) are the most malignant brain tumors. Patients rarely survive more than a year after the initial diagnosis, primarily due to the highly infiltrative/invasive behavior of these tumors, and their resistance to chemotherapy. The proposed studies arise from our efforts to understand the invasive properties of gliomas as an approach to identify unique therapeutic targets. One of the targets we have identified is Secreted Protein Acidic and Rich in Cysteine (SPARC), which is a matricellular protein that is secreted into the extracellular matrix. We have demonstrated that SPARC is highly expressed in gliomas, and that it promotes glioma invasion in vitro and in vivo. Furthermore, we found that SPARC induces migration and invasion via the activation of p38 MAPK-MAPKAPK2-HSP27 signaling pathway. HSP27 is a member of the small heat shock proteins that function to modulate the actin cytoskeleton and migration. We have demonstrated that inhibition of HSP27 suppresses SPARC-induced changes in cell morphology, migration and invasion in vitro in PTEN- null glioma cells. We have also demonstrated that the re-expression of PTEN, a tumor suppressor gene commonly lost or mutated in glioblastomas, suppresses SPARC-induced migration in vitro and invasion in vivo. We therefore propose that PTEN loss enables SPARC-induced migration and invasion via phosphorylation of HSP27. To test this hypothesis we propose the following aims.
SPECIFIC AIM 1 : Characterize SPARC- induced activation of HSP27 in the absence or presence of PTEN in cell lines and human tissues.
SPECIFIC AIM 2 : Determine whether inhibition of HSP27 alone, or in combination with radiation and/or chemotherapy, reduces tumor survival in vitro using tumor cells with different SPARC and PTEN status.
SPECIFIC AIM 3 : Determine whether inhibition of HSP27 alone, or in combination with radiation and/or chemotherapy, reduces SPARC-induced tumor cell invasion and survival in vivo and increases animal survival, using tumor cells with different PTEN status. We propose that pHSP27 inhibition in the commonly occurring SPARC-positive, PTEN-deleted GBMs can have a significant impact on inhibiting glioma cell invasion and is an important clinical strategy for glioma patients.
SPARC promotes glioblastoma invasion in vitro and in vivo by activating a signaling pathway that increases phosphorylation of HSP27, and PTEN is a tumor suppressor gene that suppresses SPARC-induced migration in vitro and in vivo. We propose that the loss of PTEN, commonly observed in glioblastomas, promotes HSP27 phosphorylation by SPARC, commonly upregulated in glioblastomas. We propose that these studies will demonstrate that pHSP27 inhibition in the commonly occurring SPARC-positive, PTEN-deleted GBMs can have a significant impact on inhibiting glioma cell invasion and is an important clinical strategy for glioma patients.
|Thomas, Stacey L; Schultz, Chad R; Mouzon, Ezekiell et al. (2015) Loss of Sparc in p53-null Astrocytes Promotes Macrophage Activation and Phagocytosis Resulting in Decreased Tumor Size and Tumor Cell Survival. Brain Pathol 25:391-400|
|McClung, Heather M; Golembieski, William A; Schultz, Chad R et al. (2012) Deletion of the SPARC acidic domain or EGF-like module reduces SPARC-induced migration and signaling through p38 MAPK/HSP27 in glioma. Carcinogenesis 33:275-84|
|Schultz, Chad R; Golembieski, William A; King, Daniel A et al. (2012) Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival. Mol Cancer 11:20|