Analysis of the molecular mechanisms underlying the role of SREBP in tumour development and progression

• Applicant: Professorin Dr. Almut Schulze
• Subject Area: Cell Biology ; Biochemistry
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267194720

Cancer remains one of the major burdens to human health. While considerable progress has been made in the development of targeted and immune therapies, limited efficacy and treatment resistance in some cancer types still creates an urgent need for new therapeutic approaches. Work over the past decade has established that cancer cells reprogram their intermediate metabolism in order to fulfil the increased demand for macromolecules for rapid growth and proliferation. Metabolic processes therefore represent targetable entities for cancer therapy.Lipids are a highly diverse class of molecules with multiple cellular functions as components of biological membranes, for energy storage and as substrates for the synthesis of signalling molecules. Lipid synthesis is controlled by the sterol regulatory element binding proteins 1 and 2 (SREBP1/2), a class of helix-loop-helix transcription factors. We have shown that SREBP1/2 are activated downstream of the Akt/mTORC1 signalling axis, one of the most important oncogenic pathways in cancer. In cancer cells, fatty acid biosynthesis and modification is essential for cell growth and to prevent the activation of cellular stress response pathways that limit tumour expansion. While this work demonstrated the importance of SREBP1/2 in cancer, the exact role of these transcription factors in cell transformation and tumour formation is only partially understood. In particular, it is not known to which extent SREBP1/2 contributes to cell-cell communication in the tumour microenvironment. Moreover, it is not known whether SREBP1/2 have additional functions in stem-like cells that contribute to treatment resistance and recurrence.During the first funding period, we analysed the role of SREBP1 in human glioblastoma (GB), a cancer type closely associated with activation of Akt/mTORC1 signalling. We found that SREBP1 promotes cell migration and angiogenesis. We also established the gene expression network controlled by SREBP1 and identified enzymes controlling the formation of lipid mediators as SREBP1 target genes in GB cells. This analysis also showed that SREBP1 inhibition triggers cytokine secretion reminiscent of cellular senescence. Furthermore, we obtained evidence for a role of SREBP1 in the maintenance of glioma stem-like cells, a cell population characterised by high treatment resistance. Finally we explored the regulation of SREBP1 activity by SOAT1, an established drug target involved in cholesterol metabolism.We now propose to extend these studies to define the exact mechanism by which SREBP1 regulates migration and angiogenesis in GB tumours. Furthermore, we want to explore cytokine secretion and potential induction of senescence following SREBP1 inhibition and study the role of SREBP1 in the maintenance of glioma stem-like cells. Together with our previous findings, this project will determine the molecular functions of SREBP1 in GB tumours and define potential targets for therapeutic development.

• DFG Programme: Research Grants