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Research Overview

Research in the Cancer Research Unit (CRU) aims to provide insights to molecular aspects of cancer biology that can be leveraged in the development of innovative diagnostic tools and improved cancer treatment strategies.

A central focus is the mechanisms that function to maintain the integrity of chromosome end structures called telomeres. Telomeres are lost in normal cells as they divide, which limits their ability to proliferate. In most cancers, telomere loss is overcome by activation of a telomere maintenance mechanism, involving an enzyme called telomerase or a process called Alternative Lengthening of Telomeres (ALT). The activation of a TMM provides cancer cells with unlimited ability to replicate (cellular immortality), and thus presents an important mechanism for therapeutic targeting. The CRU has a strong history of discoveries in telomere biology, including the discovery of the Alternative Lengthening of Telomere (ALT) mechanism in 1996 and the development of ALT detection methods that have been extensively applied by researchers across the world in studies of diverse cancer types. Current work in the CRU continues to investigate TMMs in cancer, with overarching aim to provide insights that can be applied in development of more effective cancer treatments.

In recent years, the CRU has integrated proteomic analyses as a powerful tool for discovery-based research and translation of telomere biology to clinical application. We apply proteomics, in conjunction with other ‘omic approaches to discover therapeutic targets, biomarkers and molecular vulnerabilities in cancer cells. Research in the CRU spans a broad spectrum of adult and paediatric cancers, with particular focus on ALT-driven cancers such as sarcomas and glioblastoma, as well as haematologic disorders.

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Focused, translational-oriented research is needed to advance these discoveries to the next stages, where they can be useful to patients, and that’s where we are right now. However, we also need basic, curiosity-driven research to continue if we are to make the truly great discoveries. CMRI’s culture has long been supportive of both types of research.”

Roger Reddel
Head of the Cancer Research Unit

Lab Head

Roger Reddel

Prof Roger Reddel

Professor Roger Reddel AO, BSc (Med) MBBS PhD FRACP FAAHMS FAA, Director of CMRI and Head, Cancer Research Unit, Co-Director ProCan
Available for Student Supervision

Director of CMRI, Co-Director of ProCan, and Head of the Cancer Research Unit

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Team Members

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Karen MacKenzie
Project Manager

Project Manager, Cancer Research Unit

Dale
Dale Cross
Research Assistant
Shawn
Shawn Wu
PhD Student
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Jane Noble
Senior Research Officer
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Emma Boys
Medical Oncologist and PhD Student
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Baylee Edlundh
Research Assistant

Research Projects

Molecular vulnerabilities and biomarkers of telomere maintenance states for exploitation in cancer treatment

Therapies targeted at telomere lengthening mechanisms are expected to be a very effective and specific way of treating cancer. To provide a resource for exploiting telomere biology in cancer diagnosis and treatment, the CRU has characterised telomere maintenance mechanisms in approximately 1000 cancer-derived cell lines, representing more than 30 different types of cancers. This project, completed in collaboration with the Welcome-Sanger Institute (Cambridge UK), provides a dataset of telomere biology measures of unprecedented scale that uncovers under-appreciated complexity of telomere maintenance states in cancer. The CRU have used this dataset, in conjunction with proteomic data generated by ProCan® and other ‘omic data sets, to identify cancer cell vulnerabilities, therapeutics and biomarkers associated with telomere biology. The outcome of these studies will be applied in the development of therapeutic approaches for precision medicine cancer treatment.

Understanding the ALT mechanism in cancer 

Since the CRU discovered the ALT mechanism in 1996, it has proven far more difficult to understand than telomerase. ALT involves complex networks of genes required for DNA repair and chromosomal structure. Three key players for ALT have been identified (ATRX/DAX/His3.3), but investigations indicate that there is more to be discovered in this space. The CRU is using the C-circle assay (discovered in the CRU), proteomics and next generation genomic sequencing to further interrogate the ALT mechanism. These investigations utilise isogenic panels of cell lines the team has engineered over the past decade, while also leveraging the Group’s more recent 1000 cell line study, as well as emerging data from ongoing studies of cell lines and tumour tissue derived from ALT cancers such as osteosarcoma, Ewing sarcoma and brain cancers.

Proteomic profiling for improved health outcomes in multiple myeloma

Despite the availability of new drugs and cell therapies, multiple myeloma remains an incurable disease, with treatment failure, disease evolution and high rates of relapse being the primary causes of fatality. To improve survival of patients with multiple myeloma, more sophisticated diagnostic methods are needed to precisely classify disease subsets, predict therapy response and identify the treatment most likely to cure the disease in individual patients. Toward this goal, the CRU is working to establish methodology and reference data sets for pioneering the application of state-of-the-art protein profiling (proteomics) technology in the diagnosis and classification of multiple myeloma.

Publications

Telomere elongation in immortal human cells without detectable telomerase activity.

Bryan TM, Englezou A, Gupta J, Bacchetti S and Reddel RR. EMBO J. 1995, 14: 4240-4248. PMID: 7556065.

Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines.

Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA and Reddel RR. Nature Med. 1997, 3: 1271-1274. PMID: 9359704

Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types.

Kilian A, Bowtell DDL, Abud HE, Hime GR, Venter DJ, Keese PK, Duncan EL, Reddel RR and Jefferson RA. Hum. Mol. Genet. 1997, 6: 2011-2019. PMID: 9328464

Telomere maintenance by recombination in human cells.

Dunham MA, Neumann AA, Fasching CL and Reddel RR. Nature Genet. 2000, 26: 447-450. PMID: 11101843

Protein composition of catalytically active human telomerase from immortal cells.

Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ and Reddel RR. Science 2007, 315: 1850-3. PMID: 17395830

Alternative lengthening of telomeres: models, mechanisms, and implications.

Cesare, A.J. and Reddel, R.R.: Nature Rev. Genet., 11: 319-330, 2010.

DNA C-circles are specific and quantifiable markers for alternative-lengthening-of-telomeres activity.

Henson, J.D., Cao, Y., Huschtscha, L.I., Chang, A.C., Au, A.Y.M., Pickett, H.A. and Reddel, R.R.: Nature Biotechnol., 27: 1181-1185, 2009.

R.R.: Extensive proliferation of human cancer cells with ever-shorter telomeres.

Dagg, R.A., Pickett, H.A., Neumann, A.A., Napier, C.E., Henson, J.D., Teber, E.T., Arthur, J.W., Reynolds, C.P., Murray, J., Haber, M., Sobinoff, A.P., Lau, L.M.S. and Reddel, Cell Rep. 19: 2544-2556, 2017.

Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency.

Han, M., Napier, C.E., Frölich, S., Teber, E., Wong, T., Noble, J.R., Choi, E.H.Y., Everett, R.D., Cesare, A.J. and Reddel, R.R.: J Cell Sci. 132: jcs.222349, 2019.

Addressing the challenges of high-throughput cancer tissue proteomics for clinical application

Tully, B., Balleine, R.L., Hains, P.G., Zhong, Q., Reddel, R.R. and Robinson, P.J ProCan®. Proteomics, e1900109, 2019.

Strategies to enable large-scale proteomics for reproducible research. Nature Commun.,

Poulos, R.C., Hains, P.G., Shah, R., Lucas, N., Xavier, D., Manda, S.S., Anees, A., Koh, J.M.S., Mahboob, S., Wittman, M., Williams, S.G., Sykes, E.K., Hecker, M., Dausmann, M., Wouters, M.A., Ashman, K., Yang, J., Wild, P.J., deFazio, A., Balleine, R.L., Tully, B., Aebersold, R., Speed, T.P., Liu, Y., Reddel, R.R., Robinson, P.J. and Zhong, Q.: Nature Commun., 11:3793, 2020.

All publications by R Reddel.

See the Full NCBI Bibliography.

Major Achievements

1988

Cancer Research Unit formed at CMRI. Goal: to understand cancer cell immortalisation in sufficient detail to find new cancer therapies.

1995

Discovered Alternative Lengthening of Telomeres (ALT) mechanism of telomere maintenance in cancer, opening up a new field of research.

1999

Found diagnostic marker for ALT, called APBs. Also showed that unknown factors in normal cells can repress ALT cancers.

2000

Demonstrated that ALT involves DNA recombination.

2007

First in world to identify the composition of active telomerase enzyme complex in human cells.

2009


Developed C-circle assay for measuring ALT activity in cancer. Discovered telomere trimming mechanism that could one day be exploited to target and kill cancer cells.

2011

C-circle assay licensed for research use as a test for ALT cancers. Also determined the number of ‘frayed’ telomere ends needed to signal senescence or cell aging.

2012


Involved in international Starr Consortium study identifying key genetic change (loss of ATRX) in ALT.

2013


Demonstrated that ALT has a normal counterpart in mouse cells, which also provides a new model system for studying the ALT mechanism.

2017

Discovery and characterization of cancers that grow with ever shortening telomeres.

2019

Development of an innovative approach to halting growth of ALT-driven cancers using cytolytic HSV.

What’s Next

Application of multi-omic approaches to analyse telomere maintenance mechanisms in cancer.

Develop cancer therapeutics that target vulnerabilities created by activation of telomere maintenance mechanisms.