Ubiquitin signaling in the pathogenesis and radiotherapy of glioblastoma
About the research:
Glioblastoma accounts for more than 4000 deaths every year in the UK. The cornerstone of glioblastoma treatment is constituted by maximal surgical resection, radiotherapy and chemotherapy. The therapy has not changed from the 70’ and doctors are in dire need of novel targets and compounds to increase patient survival. Indeed, the prognosis remain dismal with an overall survival of 12-15 months after diagnosis. The D’Angiolella laboratory uses mass spectrometry, clustered regularly interspaced short palindromic repeats (CRISPR), biochemistry and cell biology techniques to investigate the role of the Ubiquitin-Proteaome System (UPS) in glioblastoma development.
The UPS uses the small molecule ubiquitin to tag proteins in the cells and direct their fate. Given the role of the UPS as a master regulator of protein levels, it has a crucial role in cell survival. The UPS is amenable to specific chemical activation and inhibition, however, the role of individual UPS components as targets in glioblastoma development and response to radiotherapy is not fully explored. The laboratory has performed high resolution CRISPR screens to identify therapeutic vulnerabilities of glioblastoma in combination with radiotherapy. Students will elucidate the role of E3 ubiquitin ligases and other UPS components identified in the screen. These proteins will represent potential targets to exploit for the treatment of glioblastoma to improve radiotherapy.
The candidates enrolled will be trained in ‘state of art’ techniques such as CRISPR based methodologies, Mass Spectrometry, in vitro biochemical assays and high content microscopy. The laboratory offers the possibility to attend international courses (EMBO and others) to further refine microscopy and cell biology techniques. Attendance to one international conference during the studies is guaranteed.
1: Humphreys LM, Smith P, Chen Z, Fouad S, D'Angiolella V. The role of E3 ubiquitin ligases in the development and progression of glioblastoma. Cell Death Differ. 2021 Feb;28(2):522-537. doi: 10.1038/s41418-020-00696-6. Epub 2021 Jan PMID: 33432111; PMCID: PMC7862665.
2: Fouad S, Wells OS, Hill MA, D'Angiolella V. Cullin Ring Ubiquitin Ligases (CRLs) in Cancer: Responses to Ionizing Radiation (IR) Treatment. Front Physiol. 2019 Oct 1;10:1144. doi: 10.3389/fphys.2019.01144. PMID: 31632280; PMCID: PMC6781834.
3: Burdova K, Yang H, Faedda R, Hume S, Chauhan J, Ebner D, Kessler BM, Vendrell I, Drewry DH, Wells CI, Hatch SB, Dianov GL, Buffa FM, D'Angiolella V. E2F1 proteolysis via SCF-cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition. EMBO J. 2019 Oct 15;38(20):e101443. doi:10.15252/embj.2018101443