Elucidating the Role of Unconventional Protein Secretion in Glioblastoma

胶质母细胞瘤（GB）是一种侵袭性脑癌，预后差，治疗选择有限。这种肿瘤类型的特征在于GB细胞与其微环境之间的强烈通信，主要通过GB细胞分泌蛋白质和其他因子介导。至于其他实体瘤，胶质母细胞瘤的一个主要特征是其与其微环境（特别是神经元）的强烈相互作用，这些相互作用通过表面因子、细胞外基质、分泌蛋白和外泌体囊泡发生。因此，控制GB细胞分泌活性的细胞机制在癌症和脑细胞功能中特别重要。Galli和Demetriades实验室最近都独立地确定了专门管理UPS的两个关键参与者：i）mTORC 1-GRASP 55信号传导轴，作为响应营养和应激刺激以控制UPS的中央代谢传感器，从而重塑细胞外蛋白质组（CD实验室）;和ii）ER和线粒体蛋白的VAMP 7和自噬依赖性晚期内体分泌，以及响应mTORC 1活性的前肽（TG实验室）。有趣的是，对这些数据集的仔细荟萃分析表明，VAMP 7，GRASP 55和该过程的核心调节因子可能是相同或相关分泌途径的一部分，这促使我们在这项工作中加入力量。虽然这种非常规的分泌途径已经成为多种细胞功能和细胞和生物体内平衡的重要调节剂，但它们在胶质母细胞瘤中的作用仍然知之甚少。在这个建议中，我们建立在我们最近的发现和联合收割机我们互补的理论和技术专长，目的是了解：什么是非常规的分泌途径在胶质母细胞瘤中的作用？我们的首要目标是研究GB细胞中GRASP 55和VAMP 7依赖性UPS的基本细胞机制。此外，我们将使用相关的共培养和体内模型研究这些关键的细胞过程在GB细胞与神经元的通信以及GB肿瘤进展中的作用。这两个合作小组具有强大的协同潜力，该项目将通过ANR-DFG计划从可预见的合作中受益匪浅。总的来说，这项工作将提高我们对GB细胞如何利用神经元和非神经元非常规分泌途径扰乱宿主微环境的理解，并将揭示未来靶向胶质母细胞瘤的新方法。

Glioblastoma (GB) is an aggressive brain cancer with poor prognosis and limited therapeutic options. This tumour type is characterized by intense communication between the GB cells and its microenvironment, mediated mainly through the secretion of proteins and other factors from the GB cells. As for other solid tumours, a main characteristic of glioblastoma is its intense reciprocal interactions with its microenvironment—particularly neurons—which take place through surface factors, extracellular matrix, secreted proteins, and exosomal vesicles. Therefore, the cellular mechanisms that control secretory activity in GB cells are particularly important in cancer and in brain cell function. Both the Galli and the Demetriades labs have recently independently identified two key players that specifically govern UPS: i) the mTORC1-GRASP55 signalling axis, functioning as an central metabolic sensor that responds to nutrient and stress stimuli to control UPS, thereby reshaping the extracellular proteome (CD lab); and ii) the VAMP7- and autophagy-dependent late endosomal secretion of ER and mitochondrial proteins, as well as a pro-peptide in response to mTORC1 activity (TG lab). Interestingly, a careful meta-analysis of these datasets suggests that VAMP7, GRASP55, and core regulators of this process may be part of the same or related secretory pathways, which prompted us to join forces in this endeavour. Although such unconventional secretion pathways have emerged as crucial regulators of multiple cellular functions and cellular and organismal homeostasis, their role in glioblastoma remains poorly understood. In this proposal, we build upon our recent discoveries and combine our complementary theoretical and technical expertise, with the aim to understand: What is the role of unconventional secretion pathways in glioblastoma? Our overarching goal is to investigate the fundamental cellular mechanisms of the GRASP55- and VAMP7-dependent UPS in GB cells. Moreover, we will study the role of these crucial cellular processes in the communication of GB cells with neurons as well as in GB tumour progression using relevant co-culture and in vivo models. The two collaborating groups present strong synergistic potential, and the project will massively benefit from the foreseeable collaboration through this ANR-DFG program. Overall, this work will improve our understanding of how GB cells exploit neuronal and non-neuronal unconventional secretory pathways to perturb the host microenvironment and will reveal new means to pharmacologically target glioblastoma in the future.