Elucidating the Role of Unconventional Protein Secretion in Glioblastoma

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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.