Abstract 2467: Podoplanin expressing cancer stem cells show increased resistance to DNA damage induced by ionizing radiation

Abstract

Abstract The majority of patients with malignant gliomas, the most common and most lethal brain tumor, develop disease recurrence despite aggressive, multi-modality therapies. This treatment resistance has been attributed to a small population of tumor-initiating glioma cancer stem cells (GSCs). We recently described a new marker of GSCs, the transmembrane glycoprotein podoplanin (pdpn), based on analysis of gene expression profiling data and have found it to be more accurately identify the stem cell population than other described markers. Pdpn expression correlates with poor patient survival and decreased response to radiotherapy. Pdpn expressing cells form neurospheres at high rates in vitro, are more resistant to ionizing radiation, and initiate tumors in vivo. Silencing of pdpn leads to increased radiosensitivity. To identify the mechanism of radiation resistance in pdpn-expressing GSCs, we screened for putative binding partners and identified target of myb-like-1 (tom1l1), a known regulator of Src-pathway activation. We hypothesized that modulation of pdpn and/or tom1l1 expression would lead to alternations in the response of GSCs to radiation via src signaling. Mechanisms of radiation resistance in GSCs are poorly understood to date and the role of src family kinases in modulating radiosensitivity has not previously been reported in gliomas. Pdpn binding of tom1l1 was confirmed by co-immunoprecipation and src activation monitored by immunoblot. Pdpn and tom1l1 expression was downregulated by RNA interference and dsDNA damage and repair assayed by neutral comet assay and by scoring of γH2AX foci. Silencing of pdpn in primary culture, neurophere forming GSC-like cells resulted in increased DNA damage following 2 and 6 Gy ionizing radiation. We similarly examined effects of decreased tom1l1 to determine if the effects on DNA repair mediating by pdpn were acting via the src pathway. In summary, our data suggest that pdpn expression correlates with increased dsDNA repair following ionizing radiation and presents a possible mechanism by which GSCs resist treatment and regrow the tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2467. doi:10.1158/1538-7445.AM2011-2467