Glioblastoma is the most prevalent and aggressive malignant brain tumor in adults, hallmarked by a high infiltration propensity and rapid invasion to the surrounding brain tissues. This makes surgical resection, followed by radiation and pharmacological therapies, poorly effective, resulting into a short (1.5 year) median survival-time. Glioblastoma cell-motility is strictly controlled by an entangled network of interacting proteins and signaling cascades, whose deregulation contributes to cancer progression and malignancy.
In this project, we focus on prominent members of this intricate network such as selected Rho GTPases (Cdc42, Rac1, RhoA) proteins, the Arp2/3 machinery, all critically entailed in glioblastoma invasion and spreading, as well on the the secondary-active Na–K–Cl cotransporter 1 (NKCC1), which ensuring the electroneutral movement of Cl–, Na+, and K+ ions across cellular membranes, regulates Cl homeostasis and cell volume. We are studying the molecular mechanisms underlying the actin cytoskeleton and cell volume remodeling and the mechanism of already approved drugs targeting the above-mentioned proteins. The project is financed by a ARES CUP: POR FESR 2014 2020 – 1.3.b – Friuli Venezia Giulia and by the AIRC fellowship awarded to dr. Angela Parise. The project is in collaboration with Prof. D. Cesselli, University of Udine, Italy, Prof. V. Torres, SISSA, Italy, the industrial companies Exact Lab and Scientific Research Center Dott. Dino Paladin.
Key publications
Janoš, P. & Magistrato, A. All-Atom Simulations Uncover the Molecular Terms of the NKCC1 Transport Mechanism. J. Chem. Inf. Model. 61, 3649–3658 (2021).
Laporte, S. & Magistrato, A. Deciphering the Molecular Terms of Arp2/3 Allosteric Regulation from All-Atom Simulations and Dynamical Network Theory. J. Phys. Chem. Lett. 12, 5384–5389 (2021).
Xu, J. et al. Molecular Mechanisms of the Blockage of Glioblastoma Motility. J. Chem. Inf. Model. 61, 2967–2980 (2021).
Magistrato Lab 