Role of heparan sulphate in breast cancer pathogenesis
PD Dr. Martin Götte
Successful applicants will aim at the detailed molecular analysis of the structural requirements and functional effects of heparan sulphate deregulation in breast cancer pathogenesis. The projects include the analysis of structural alterations in heparan sulphate (proteoglycans) in breast cancer cells, and their functional consequences on a cancer stem cell phenotype and the therapeutically relevant resistance of breast cancer cells to radiation therapy.
Additional projects in the field of inflammation research (in cooperation with the group of Seidler) and other areas of glycobiology are possible, (see interests of PD Dr. Götte under ‘members’). Own project suggestions are encouraged.
Possible PhD projects include
- Role of heparan sulfate patterns in cancer stem cell function
Data from our laboratory have demonstrated that altered expression of the heparan sulphate proteoglycan Syndecan-1, and alterations in the sulfation pattern of heparan sulphate in breast cancer cells lead to a dysregulation of a cancer stem cell phenotype (Ibrahim et al., submitted & unpublished data). Stemness-related properties of cancer cells such as increased expression of ABC transporters are linked to disease recurrence and are thus of major translational relevance. In the proposed project, the impact of altered HS patterns on the cancer stem cell phenotype and on stemness-related signaling pathways, including the Notch pathway and cytokine-mediated pathways will be studied in collaboration with Dr. Suresh in Hyderabad. Human breast cancer cell lines will be stably transfected with plasmids designed for the overexpression of heparan sulphate sulfotransferases. Successful transfection will be monitored by real-time PCR, GAG epitope staining HPLC analysis of HS and mass spectrometric analysis in cooperation with the group of Dr. Mormann. Stemness-related assays include flow cytometric analysis of marker expression and mammosphere formation assays. Ligand interactions with altered vs control HS patterns will be investigated in collaboration with Prof. Swamy (UoH).
- Role of the HS proteoglycan Syndecan-1 in breast cancer cell resistance to radiotherapy.
The cell surface heparan sulphate proteoglycan syndecan-1 is a prognostic marker in breast cancer and modulates tumor progression at multiple molecular levels. Recent results from our group have revealed a novel and unexpected role for the heparan sulphate proetoglycan Syndecan-1 in the resistance of breast cancer cells to radiation therapy (Hassan et al. FEBS J. 2013). In the proposed project, we will study Syndecan-1-dependent tumor cell resistance to radiotherapy in molecular detail focusing on integrin- vs cytokine-mediated signal transduction pathways using pharmacological inhibitors of selected signalling pathways. Relevant Syndecan-1-binding ligands will be identified, their impact on radiation resistance will be determined in vitro by colony formation assays and flow cytometric techniques, and their molecular interactions will be studied with Prof. Swamy (UoH). The functional impact of the HS chain in this process will be defined employing Syndecan-1-derived HS purified in collaboration with the groups of PD Dr. Seidler and Dr. Mormann.
Last update: 29.04.2013
