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 strategic oncogenic E3 ligases?
- What are the key determinants of cancer sex-disparity?
- Which are the main regulatory pathways driving oncogenic mutant p53 in cancer?
- What is the role of p53 in determining cancer immune profile and the response to cancer immunotherapy?
Discovery of key determinant of cancer sex disparity
Sex-disparities in cancer frequency and survival is well established across the globe but remain inadequately understood. Strikingly in men, non-reproductive cancer incidence is higher and mortality rates are nearly double those of women. This can only partially be explained by sex hormones and lifestyles. These differences imply that anti-cancer defence mechanisms may not function with the same proficiency between the sexes. Using bioinformatics approaches we recently uncovered that mutations in the major tumour suppressor gene TP53 (encoding p53 protein) are more prevalent in men than in women in the majority of non-reproductive cancers. We also uncovered that the gene networks governed by p53 function less efficiently in men than in women. Building on these discoveries we are exploring in detail the impact of p53 on cancer sex disparities in multiple non-reproductive cancers using bioinformatics approaches and our pre-clinical models.
- VCCC Lunchtime Live Presentation (2021.6.7): https://www.youtube.com/watch?v=1BkPlnx8U7E
- Interview with on the ABC RN Radio Health Report with Tegan Taylor (2021.6.7): https://www.abc.net.au/radionational/programs/healthreport/should-biological-sex-be-considered-in-cancer-care/13376864
- Interview with on the ABC RN Radio Health Report with Dr Norman Swan (2019.12.2): https://www.abc.net.au/radionational/programs/healthreport/sex-differences-in-cancer/11757050
Can we therapeutically restore tumour suppression by targeting key oncogenic E3 ligases?
A frequent event driving cancer is the loss of function of tumour suppressors due to their excessive degradation by E3 ubiquitin ligases. Our pioneering studies established this phenomenon for p53 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 and breast cancers we adopted proteomic and genomic discovery approaches and have applied computational and bioinformatics analyses. We identified novel vital tumour suppression pathways. We are currently exploring the role of key candidates using genetic approaches in culture, sophisticated pre-clinical mouse models, and human samples to test the efficacy of restoring tumour suppression 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 new 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 carried genome-wide ‘loss of function’ screens (siRNA, miRNA, lncRNA), and combined these with bioinformatics analyses to identify novel regulators of mutant p53. We are currently characterizing novel regulators of mutant p53, exploring their mechanisms of action and develop novel approaches to target mutant p53 in cancer.
Selected recent publications:
Haupt S, Caramia F, Klein, S.L., Rubin J.R., Haupt Y. 2021 Sex disparities matter in cancer development and therapy. Nature Reviews Cancer; Jun;21(6):393-407. doi: 10.1038/s41568-021-00348-y; PMID: 33879867Nature Reviews Cancer
Haupt S, Haupt Y (2021) Cancer and Tumour Suppressor p53 Encounters at the Juncture of Sex Disparity. Frontiers in Genetics12:632719
Donald Freudenstein, Cassandra Litchfield, Franco Caramia, Gavin Wright, Benjamin J. Solomon, David Ball, Simon P. Keam, Paul Neeson, Ygal Haupt, Sue Haupt, TP53 Status, Patient Sex, and the Immune Response as Determinants of Lung Cancer Patient Survival. Cancers 2020 Jun; 12(6): 1535; doi:10.3390/cancers12061535; PMID: 32545367
Haupt S, Caramia F., S, Soussi T., Lozano G., Chen H., Liang H., Speed TP., and Haupt Y (2019). Identification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network. Nat. Commun. 26(10):5385.
Gamell C, Bandilovska I, Gulati T, Kogan A, Lim SC, Kovacevic Z, Takano EA, Timpone C, Agupitan AD, Litchfield C, Blandino G, Horvath LG, Fox SB, Williams SG, Russo A, Gallo E, Paul PJ, Mitchell C, Sandhu S, Keam SP, Haupt S, Richardson DR, Haupt Y. E6AP Promotes a Metastatic Phenotype in Prostate Cancer. iScience. 2019 Dec 20;22:1-15. doi: 10.1016/j.isci.2019.10.065.
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.
The Tumour Suppression 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:
Exploring the explanation for cancer sex disparity
We recently discovered a role for p53 in sex disparity in non-reproductive cancers. In this project the student will explore the mechanism by which p53 impacts on cancer sex disparity and will identify p53-related signatures with which to better diagnose cancer in sex specific manner. This project is divided into two:
- A bioinformatic approach, in which the candidate is expected to have knowledge in computational biology and bioinformatics.
- A wet lab-based project in which the student will test our hypotheses in culture and in pre-clinical models.
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 test the therapeutic efficacy of targeting these regulators to treat mutant p53 cancers.
Restoration of tumour suppression by targeting specific E3 ubiquitin ligases.
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.
To gain insight into the regulation of mutant p53, we undertook multiple loss of function, whole genome 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.