The Haupt laboratory explores novel regulatory pathways governing tumour suppressors.
Our research aims to answer the following questions:
- Can we therapeutically restore tumour suppression by targeting key oncogenic E3 ligases?
- Which are the key regulatory pathways of oncogenic mutant p53 in cancer?
- Do tumour suppressors affect responses to cancer immunotherapy?
- To what extent do tumour suppressors impact cancer sex-disparity?
Can we therapeutically restore tumour suppression by targeting key oncogenic E3 ligases?
A frequent event in cancer is the loss of function of tumour suppressor molecules due to their excessive degradation by E3 ubiquitin ligases. Our pioneering studies established this phenomenon for the p53 tumour suppressor and its E3 ligase complex Mdm2/MDM4, and with the tumour suppressors PML/p27 and their E3 ligase E6AP. To discover key tumour suppressive pathways in prostate cancer we adopted proteomic and genomic discovery approaches and have applied computational and bioinformatics analyses to identify vital tumour suppressor pathways. We combine thes approaches with a targeted approach directed to the p53 signalling pathway. We are currently exploring the role of key candidates using 2D and 3D cell based cultures, sophisticated pre-clinical mouse models, and human samples. In collaboration with our clinician collaborators, Profs. Scott Williams, Ben Solomon and Shahneen Sandhu, we have access to unique cancer samples, which we will use to test our hypothesis that tumour suppression can be restored by targeting key E3 ligases.
Which are the key regulatory pathways of oncogenic mutant p53 in cancer?
Mutations in p53 occur in half the cases of human cancer. Missense mutations in p53 lead not only to the loss of wt p53 function, but critically also to the acquisition of neomorphic, oncogenic gain of functions (GOFs), which drive cancer progression and metastasis. Detailed knowledge of mutant p53 regulation is essential for our understanding of cancer biology, and for the design of novel therapeutics. We have developed discovery approaches using functional genome-wide ‘loss of function’ screens (siRNA, miRNA, lncRNA), and combined these with bioinformatics analyses to identify novel regulators of mutant p53. We build on the output of these screens to define novel regulators of mutant p53, explore their mechanisms of action and develop novel approaches to target mutant p53 in cancer.
Gulati T, Huang C, Caramia F, Raghu D, Paul PJ, Goode RJA, Keam SP, Williams SG, Haupt S, Kleifeld O, Schittenhelm RB, Gamell C, Haupt Y (2018). Proteotranscriptomic measurements of E6-Associated Protein (E6AP) targets in DU145 prostate cancer cells. Molecular & Cellular Proteomics. 17(6): 1170-1183.
Gamell C, Gulati T, Levav-Cohen Y, Young R, Do H, Pilling P, Takano E, Watkins N, Fox SB, Russell PA, Ginsberg D, Monahan BJ, Wright G, Dobrovic A, Haupt S, Solomon B, Haupt Y (2017). Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decrease expression of the INK4/ARF locus in non-small cell lung cancer. Sci Signal. 10(461):eaaf8223.
Miranda PJ, Buckley D, Raghu D, Pang JM, Takano EA, Vijayakumaran Teunisse FAS, Posner A, Procter T, Herold MJ, Gamell C, Fox SB, Jochemsen A, Haupt S, Haupt Y (2017). MDM4 is a rational target for treating breast cancers with mutant p53. J Pathol. 241(5):661-670.
Paul PJ, Raghu D, Chan AL, Gulati T, Lambeth L, Takano E, Herold MJ, Hagekyriakou J, Vessella RL, Fedele C, Shackleton M, Williams ED, Fox S, Williams S, Haupt S, Gamell C, Haupt Y (2016). Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP. Oncogene. 35(48):6235-6245.
Wolyniec K, Jake S, de Stanchina E, Levav-Cohen Y, Alsheich-Bartok O, Louria-Hayon, I, Corneille V, Kumar B, Woods SJ, Opat S, Johnstone RW, Scott CL, Segal D, Pandolfi PP, Fox S, Strasser A, Jiang YH, Scott WL, Haupt S, Haupt Y (2012). E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis. Blood. 120(4):822-832.
Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T, Matentzoglu K, Jiang YH, Muller S, Scheffner M, Haupt S, Haupt Y (2009). E6AP promotes the degradation of the PML tumor suppressor. Cell Death Diff. 16(8):1156-1166.
Haupt S, di Agostino S, Mizrahi I, Alsheich-Bartok O, Voorhoeve M, Damalas A, Blandino G, Haupt Y (2009). Promyelocytic leukemia protein is required for gain of function by mutant p53. Cancer Res. 69(11):4818-4826.
The Haupt Laboratory is offering projects for Honours students, Masters students, PhD students and MD students. We seek students to undertake lab-based experimental research and/or bioinformatics based research. The following research projects are available:
Exploration of novel approaches to anti-cancer treatment: manipulation of mutant p53.
In this project the student will study key candidate regulators derived from a high content screen, to explore the regulation of mutant p53 and to define novel targets for anti-cancer drugs aimed at mutant p53. The student will explore the therapeutic efficacy of targeting these regulators to treat mutant p53 cancers.
Restoration of tumour suppression by using the ubiquitin proteasomal system as an anti-cancer approach.
In this project the student will characterize the role of key E3 ligases in evading tumour suppression in prostate and breast cancers. The student will exploit novel therapeutic opportunities directed at E3 ligases to restore tumour suppression. This project will involve a variety of molecular and biochemical assays, as well as cell culture, sophisticated pre-clinical mouse models, human samples and therapeutic approaches.
Computational analysis of regulatory pathways of mutant p53, a key driver of human cancer.
Mutant p53 is a key driver of cancer and is the most mutated gene in human cancer. However, the regulation of mutant p53 is only partially understood. To gain insight into the regulation of this key oncogene, we recently undertook multiple loss of function, whole genome high content screens (siRNA, miRNA, and lncRNA). In this project the student will perform computational and bioinformatics analyses using the data derived from these screens and from publically available data, to explore novel regulatory pathways of mutant p53. The candidate is expected to have knowledge in computational biology and in bioinformatics.