Cancer
The Cancer Research Unit conducts trailblazing work on telomeres, which are important for senescence (aging) and all cancers.
Research Overview
Our main emphasis is on understanding how cancer cells continue to proliferate using the Alternative Lengthening of Telomeres (ALT) mechanism.
Better understanding of this mechanism will enable us to develop better treatments against ALT cancers, which are some of the most aggressive types, including glioblastoma brain tumours and osteosarcomas.
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
Most of the work in the Cancer Research Unit (CRU) currently focuses on understanding telomeres and how these structures at the ends of chromosomes are maintained in cancer cells. Telomeres shorten each time a cell divides, and this acts as a countdown eventually telling cells to stop proliferating. Cancer cells are able to counteract the shortening process and continue to proliferate out of control. In order to keep growing, the cancer cells must activate the enzyme telomerase or the Alternative Lengthening of Telomeres (ALT) mechanism, either of which can counteract telomere shortening. The ALT mechanism was originally discovered by the CRU, and the team continues to focus on understanding how this mechanism works, and most importantly, how to inhibit it in order to treat cancer.
Lab Head
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
Student enquiries
[email protected]
Director of CMRI, Co-Director of ProCan, and Head of the Cancer Research Unit
Team Members
Karen MacKenzie
Project Manager
Project Manager, Cancer Research Unit
Research Projects
Telomere chromatin in ALT
We are investigating many aspects of telomere chromatin structure and telomere biology, including telomere length trimming and telomeric DNA sequences. Our aim is to understand how ALT telomeres are structured and how they differ from telomeres in normal and telomerase-positive cells. This will help us to understand the ALT mechanism in more detail and provide information on possible targets for interfering with ALT activity in cancer cells.
Genes involved in ALT
The C-circle assay for detecting ALT activity, which was developed by Jeremy Henson in our laboratory, has enabled us to search for the genes that repress ALT in normal cells. We are also using this and other techniques to find the genes needed for ALT activity. These studies will enable us to find targets for the development of ALT-inhibiting therapeutic drugs to treat cancer.
ALT in normal tissues
We have developed a way to detect ALT activity in mouse tissues by demonstrating that a DNA sequence introduced into the telomere can be copied from telomere to telomere. We are developing this technology to further study how low levels of ALT activity can become sufficiently elevated to prevent telomere shortening and allow unlimited proliferation of cancer cells.
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
Extend the utility of the C-circle assay for diagnostic use and to screen for ALT inhibitors. Study key ALT proteins to reveal potential therapeutic drug targets.