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Biochemistry (Pieters)

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Analysis of the role of the coronin 1 signalling pathway in glioblastoma through a systems medicine approach

Research Project  | 1 Project Members

Glioblastoma is the most common, highly aggressive, malignant primary brain tumour with one of the worst prognoses among aggressive cancers. Despite the development of advanced multimodal therapeutic strategies, which combine aggressive surgery, radiation, and chemotherapy, patients with glioblastoma have a dismal prognosis, with a median overall survival time of less than 18 months from the time of diagnosis. One of the main problems is that glioblastoma is a highly complex disease, with a poor understanding of the key drivers of tumorigenesis1. As a result, no specific treatment for glioblastoma is available, and patients are currently treated with a combination of surgery, radiation and chemotherapy in an attempt to non-selectively dampen cell growth. While specific molecular drivers remain largely unknown, it is believed that glioblastoma occurs as a result of modulation of diverse neuro-glioma signalling pathways and a capacity to suppress immune destruction to drive proliferation and invasion. In particular, glioblastoma is associated with a reduction of the second messenger cAMP in glioma cells and induction of T cell-mediated immunosuppression, both of which are key drivers of glioma tumour cell growth. One pathway that has recently emerged to play a key role in cell proliferation, neuronal signalling and cAMP-dependent T cell-mediated immunosuppression is the coronin 1 signalling pathway. Coronin 1 is expressed in excitatory neurons, glial cells and T cells; strikingly, preliminary data suggest highly significant downregulation of coronin 1 in biopsies from glioblastoma patients. The goal of the current research proposal is to use a systems medicine approach to dissect and analyse a role for deregulated coronin 1 signalling in glioblastoma. In particular, we will use patient-derived cells and tissues from patient cohorts, cell lines, orthotopic and xenograft mouse models to (i) analyse coronin 1-dependent glioma proliferation, migration and invasion in vitro and in vivo; (ii) analyse coronin 1-dependent (neuro) gliomal synaptic signalling; (iii) perform system-based analysis to dissect neuro-glioblastoma signalling using patient-derived xenograft murine models through the application of (phospho-) proteomics and transcriptomics; (iv) assess coronin 1-dependent immunosuppression in biopsy-isolated T cells. The coronin 1 pathway has recently emerged as an important regulator of such diverse pathways as cell proliferation, neuronal signalling and immunosuppression. However, there is no knowledge on any role for this pathway in glioblastoma. Given the high risk/high gain nature of the proposed work, we believe that the combined expertise of the applicants' laboratories together with the innovative and systems-based approaches proposed in this grant may allow the definition of hitherto unknown mechanisms driving glioblastoma. Furthermore, knowledge on the precise molecular pathways involved in glioblastoma may not only unravel the complexity of glioblastoma, but also allow specific targeting of such pathways, including methods to overcome suppression of antitumor responses, in order to foster development of innovative diagnostic, prognostic and therapeutic approaches.