Hugo DOSQUET

Unravelling the molecular basis of LRIG1-mediated RTK inhibition.
Glioblastoma (GBM) is the most aggressive and most frequent primary tumor of the human brain with an invariably fatal outcome. The majority of GBMs display genomic alterations in receptor tyrosine kinase (RTK) pathways, leading to overexpression of RTKs and an overactivation of downstream signaling. Current GBM treatment including tumor resection, chemo- and radiotherapy, only provides little survival benefit for patients, thus improved agents are needed. LRIG1 (Leucine rich repeats and immunoglobulin like domains protein 1 ) is a transmembrane protein highly expressed in brain and involved in the development of the nervous system. This transmembrane protein has been shown to downregulate RTK signaling and to act as a tumor suppressor. Previous results from our lab had shown that the soluble form of LRIG1 (sLRIG1) retains its anti-proliferative effect on GBM cells, reduces tumor growth in vivo and improves survival of mice carrying patient-derived GBMs. We recently identified the RTK AXL as a novel target of LRIG1 and a differential effect on AXL compared to EGFR. The two main goals of this PhD project are: 1) to reveal the mechanism of action of LRIG1, and 2) to identify the minimal active residue of the protein. Increasing our knowledge on LRIG1-mediated RTK inhibition in GBM cells may allow us to design a novel sLRIG1-based therapeutic for GBM patients.

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