The Walter and Eliza Hall Institute of Medical Research

Cancer

We seek to understand how different types of cancers develop, with the goal of developing more effective treatments and preventative strategies. Major areas of interest are stem cells, cytokines, cancer-provoking mutations and apoptosis (the physiologic program of cell death). Milestone discoveries include:

Discovery and clinical development of colony stimulating factors

Our studies of cytokines controlling white blood cell production have changed world-best clinical practice. The development of clonal assays for blood stem and progenitor cells led to the discovery, purification and clinical use of cytokines named colony stimulating factors (CSFs). G-CSF and GM-CSF have been used to treat over 9 million cancer patients, to stimulate white blood cell recovery following chemotherapy. The finding that G-CSF mobilises stem cells out of the bone marrow into the blood revolutionised transplantation, enabling peripheral blood stem cell transplantation.

• Bradley TR and Metcalf D (1966) Growth of mouse bone marrow cells in vitro. Aust J Exp Biol Med Sci 44 287-299.
• Nicola NA, Metcalf D, Matsumoto M, Johnson GR (1983) Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells: Identification as granulocyte colony‑stimulating factor. J Biol Chem 258: 9017-9023.
• Duhrsen U, Villeval JL, Boyd J, Kannourakis G, Morstyn G and Metcalf D (1988) Effects of recombinant human granulocyte colony stimulating factor on hematopoietic progenitor cells in cancer patients. Blood 72: 2074-2081.
• Sheridan WP, Begley CG, Juttner CA, Szer J, To LB, Maher D, McGrath KM, Morstyn G, Fox RM (1992) Effect of peripheral-blood progenitor cells mobilized by filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy. Lancet 339: 640—644.
• Morstyn G, Souza LM, Keech J, Sheridan W, Campbell L, Alton NK, Green M, Metcalf D and Fox R (1998) Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet 1: 667-672

Discovery of the SOCS proteins

The SOCS proteins (suppressors of cytokine signalling) are feedback inhibitors of cytokine action that are essential to prevent development of inflammatory and autoimmune diseases

• Starr R, Willson TA, Viney EM, Murray LJL, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387: 917-921.
• Alexander WS, Starr R, Fenner J, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TWH, Nicola NA, Hertzog PJ, Metcalf D and Hilton DJ (1999) SOCS-1 is a critical inhibitor of interferon signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell, 98: 597-608.

Discovery of Leukaemia Inhibitory Factor (LIF) and its role in maintaining the developmental potential of embryonic stem cells

The cytokine LIF proved to have diverse physiological actions. Notably, it is used worldwide to maintain mouse embryonic stem cells for genetic and regenerative studies.

• Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM (1988) Myeloid leukaemia inhibitory factor (LIF) maintains the developmental potential of embryonic stem cells. Nature 336: 684‑687.

Discovery of oncogene activation by chromosome translocation

The recurring chromosome translocation associated with human Burkitt’s lymphoma was found to activate a specific gene, myc, and studies in mice proved this to be the fundamental cause of the tumour. This work opened the way to identifying cancer-inducing genes associated with other chromosome translocations.

• Adams JM, Gerondakis S, Webb E, Corcoran LM and Cory S. (1983). Cellular myc oncogene is altered by chromosome translocation to an immunoglobulin locus in murine plasmacytomas and is rearranged similarly in human Burkitt lymphomas. Proc. Natl. Acad. Sci. USA. 80:1982-1986.
• Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, Palmiter RD and Brinster RL (1985). The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318:533-538

Discovery that bcl-2, the gene activated by chromosome translocation in human follicular lymphoma, promotes cancer formation by blocking apoptosis

Tissue homeostasis is maintained by balancing cell production and cell death. These studies showed that bcl-2 was a novel type of oncogene that promoted inappropriate cell survival rather than overproliferation.

• Vaux DL, Cory S and Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335:440-442
• Strasser A, Harris AW, Bath ML and Cory, S (1990) Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348, 331-333

Discovery that inhibition of apoptosis can profoundly perturb lymphopoiesis, leading to autoimmunity

• Strasser A, Harris AW and Cory S (1991) Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship Cell 67:889-899
• Strasser A, Whittingham S, Vaux DL, Bath ML, Adams JM, Cory S and Harris AW. (1991) Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. PNAS 88:8661-8665

Discovery and physiologic role of Bim, a key pro-apoptotic member of the Bcl-2 family

Bcl-2 has many relatives, some of which promote apoptosis. Bim and other members of the sub-family known as BH3-only proteins, regulate tissue homeostasis and serve as suppressors of cancer development and autoimmunity.

• Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Köntgen F, Adams JM, Strasser A. (1999) Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286(5445):1735-8 PMID: 11193044
• Bouillet P, Purton J F, Godfrey D I, Zhang L-C, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams J M and Strasser A. 2002. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415:922-926

Discovery of mammalian IAP proteins and their inhibitors and elucidation of their function in regulating apoptosis

The 'inhibitor of apoptosis' (IAP) proteins, first discovered in insect viruses, repress apoptosis by inhibiting the executioners of cell death (caspases), or by blocking the pathways that activate them.

• Uren, AG, Pakusch, M, Hawkins, CJ, Puls, KL and Vaux, D. (1996) Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors Proc Natl Acad Sci USA 93 (10): 4974-4978
• Verhagen, AM, Ekert, PG, Pakusch, M, Silke, J, Connolly, LM, Reid, GE, Moritz, RL, Simpson, RJ and Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins Cell 102 (1): 43-53.
• Verhagen, AM, Silke, J, Ekert, PG, Pakusch, M, Kaufmann, H, Connolly, LM, Day, CL, Tikoo, A, Burke, R, Wrobel, C, Moritz, RL, Simpson, RJ, Vaux, DL (2002). HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins J Biol Chem 277 (1): 445-454.

Discovery that platelet lifespan is dictated by the Bcl-2 family

Platelets are short-lived blood clotting cells. This discovery opens the possibility of developing a drug that improves their longevity.

• Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DC, Kile BT (2007) Programmed anuclear cell death delimits platelet life span Cell. Mar 23;128(6):1173-86

Identification of breast stem cells

This seminal study in mice showed for the first time that a fully functional breast can be generated from a single stem cell.

• Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE (2006). Generation of a functional mammary gland from a single stem cell. Nature 439(7072):84-8.