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

癌症仍然是人类健康的主要负担之一。虽然在靶向和免疫疗法的开发方面取得了相当大的进展，但某些癌症类型的有限疗效和治疗抗性仍然迫切需要新的治疗方法。过去十年的工作已经确定，癌细胞重新编程其中间代谢，以满足快速生长和增殖对大分子的需求增加。因此，代谢过程代表了癌症治疗的靶向实体。脂质是一类高度多样化的分子，具有多种细胞功能，作为生物膜的组成部分，用于能量储存，并作为合成信号分子的底物。固醇调节元件结合蛋白1和2（SREBP 1/2）是一类螺旋-环-螺旋转录因子，控制脂质的合成。我们已经证明，SREBP 1/2在Akt/mTORC 1信号传导轴下游被激活，Akt/mTORC 1信号传导轴是癌症中最重要的致癌途径之一。在癌细胞中，脂肪酸的生物合成和修饰对于细胞生长和防止限制肿瘤扩张的细胞应激反应途径的激活至关重要。虽然这项工作证明了SREBP 1/2在癌症中的重要性，但这些转录因子在细胞转化和肿瘤形成中的确切作用仅部分了解。特别是，目前尚不清楚SREBP 1/2在肿瘤微环境中对细胞间通讯的贡献程度。此外，目前尚不清楚SREBP 1/2是否在干细胞样细胞中具有额外的功能，这些功能有助于治疗抗性和复发。在第一个资助期内，我们分析了SREBP 1在人类胶质母细胞瘤（GB）中的作用，这是一种与Akt/mTORC 1信号传导激活密切相关的癌症类型。我们发现SREBP 1促进细胞迁移和血管生成。我们还建立了由SREBP 1控制的基因表达网络，并确定了GB细胞中控制脂质介质形成的酶作为SREBP 1靶基因。该分析还表明，SREBP 1抑制触发细胞因子分泌，使人联想到细胞衰老。此外，我们获得了SREBP 1在维持神经胶质瘤干细胞样细胞中的作用的证据，神经胶质瘤干细胞样细胞是一种以高治疗抗性为特征的细胞群体。最后，我们探索了SOAT 1对SREBP 1活性的调节，SOAT 1是一个参与胆固醇代谢的既定药物靶点，我们现在建议扩展这些研究，以确定SREBP 1调节GB肿瘤迁移和血管生成的确切机制。此外，我们希望探索SREBP 1抑制后细胞因子分泌和潜在的衰老诱导，并研究SREBP 1在维持胶质瘤干细胞样细胞中的作用。结合我们以前的发现，该项目将确定SREBP 1在GB肿瘤中的分子功能，并确定治疗开发的潜在靶点。

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.