The Walter and Eliza Hall Institute of Medical Research

Dr Ross Dickins

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Division: Molecular Medicine

Research Overview

Cancer results from an accumulation of genetic mutations that disable the normal regulation of cell growth and survival. The combination of mutations that promotes malignancy can vary significantly between tumours, even of the same cell type. These underlying genetic differences can also determine the response of a tumour to chemotherapy. In the last few years, advances in DNA sequencing and copy number analysis have finally allowed researchers to scan the entire genome of individual cancers for mutations that contribute to cancer development. Now the key challenge is to understand how these newly uncovered, recurrent genetic changes contribute to tumourigenesis and treatment response, as a step towards developing more effective cancer therapies.

To study cancer gene function, we have recently developed methods for stable or reversible inhibition of endogenous genes using RNA interference (RNAi). This technology allows us to examine the effects of blocking or restoring the expression of particular genes within growing tumours in mice.

Acute lymphoblastic leukemia, the most common cancer affecting children, is characterised by a block in lymphocyte differentiation. This appears to be caused by recurrent hypomorphic mutations in transcription factors (eg. Pax5 and Ikaros) that normally promote differentiation. Our laboratory is using RNAi to understand how loss of these transcription factors causes leukemia, and how these genetic changes influence response to standard chemotherapies. We are also using focused RNAi screening to identify genes that are required for the growth/survival of particular hematopoietic lineages, particularly B lymphocytes. These approaches aim to uncover gene products that are potential drug targets for B cell hyperproliferative disorders including leukemia.

Selected Publications

1. Premsrirut PK, Dow LE, Kim SY, Camiolo M, Malone CD, Miething C, Scuoppo C, Zuber J, Dickins RA, Kogan SC, Shroyer KR, Sordella R, Hannon GJ, Lowe SW. A rapid and scalable system for studying gene function in mice using conditional RNA interference. Cell. 2011 Apr 1;145(1):145-58. PMID: 21458673
2. Fellmann C, Zuber J, McJunkin K, Chang K, Malone CD, Dickins RA, Xu Q, Hengartner MO, Elledge SJ, Hannon GJ, Lowe SW. Functional Identification of Optimized RNAi Triggers Using a Massively Parallel Sensor Assay. Mol Cell. 2011 Mar 18;41(6):733-46. Epub 2011 Feb 25. PMID: 21353615
3. Takiguchi M, James C, Josefsson EC, Carmichael CL, Premsrirut PK, Lowe SW, Hamilton JR, Huang DCS, Kile BT, Dickins RA. Transgenic, inducible RNAi in megakaryocytes and platelets in mice. J Thromb Haemost, 2010 Dec;8(12):2751-6. PMID: 21138522
4. Chicas A, Wang X, Zhang C, McCurrach M, Zhao Z, Mert O, Dickins RA, Narita M, Zhang M, Lowe SW. Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell. 2010 Apr 13;17(4):376-87. PMID: 20385362 [PubMed - in process]
5. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008 Aug 22;134(4):657-67 PMID: 18724938 [PubMed - indexed for MEDLINE]
6. Dickins RA, McJunkin K, Hernando E, Premsrirut PK, Krizhanovsky V, Burgess DJ, Kim SY, Cordon-Cardo C, Zender L, Hannon GJ, Lowe SW. Tissue-specific and reversible RNA interference in transgenic mice. Nat Genet. 2007 Jul;39(7):914-21 PMID: 17572676 [PubMed - indexed for MEDLINE]
7. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007 Feb 8;445(7128):656-60 PMID: 17251933 [PubMed - indexed for MEDLINE]
8. Ramiro AR, Jankovic M, Callen E, Difilippantonio S, Chen HT, McBride KM, Eisenreich TR, Chen J, Dickins RA, Lowe SW, Nussenzweig A, Nussenzweig MC. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 2006 Mar 2;440(7080):105-9 PMID: 16400328 [PubMed - indexed for MEDLINE]
9. Dickins RA, Hemann MT, Zilfou JT, Simpson DR, Ibarra I, Hannon GJ, Lowe SW. Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nat Genet. 2005 Nov;37(11):1289-95 PMID: 16200064 [PubMed - indexed for MEDLINE]

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Current Laboratory Members

Nossal Fellow: Ross Dickins, BSc(Hons) PhD Melb

Postdoctoral Fellow: Mutlu Kartal-Kaess, MD Heidelberg

Postdoctoral Fellow: Mark McKenzie, BSc(Hons) PhD Melb

Research Technician: Sean Ivory, BSc(Hons) Melbourne

Postgraduate Student: Grace Liu, BBiomedSc(Hons) Melb

Postgraduate Student: Matthew Witkowski, BSc Melb

Scientific Coordinator/Alliance Manager: Fiona McGrath BAppSc(Hons) RMIT

Administration Officer: Etty Bonnici