Dr Melanie McConnell received a PhD in biochemistry from the University of Otago, working to understand regulation of gene expression during kidney development.
After a postdoctoral fellowship comparing normal and leukaemia blood cell development in the Ruttenberg Cancer Center at Mount Sinai School of Medicine in New York, she joined the faculty of the Division of Medicine at Mount Sinai, in the Department of Hematology and Oncology. Her research focused on the interaction between gene expression and cell biology during exposure of leukaemic cells to novel therapeutic agents, both in the laboratory and in patients.
On her return to New Zealand, Melanie established the Cell Survival Research Group at the Malaghan Institute. In 2013 she took up a position at the School of Biological Sciences at Victoria University but continues to work closely with the Institute.
Isolation and characterisation of GBM cancer stem cells
Contributors: Kate Broadley, Kathryn Farrand, Mr Martin Hunn, Dr Patries Herst, Dr Ian Hermans, Dr Melanie McConnell
Cancer cells grow under conditions of metabolic and energetic stress. During chemotherapy and radiotherapy treatments of cancer patients, these cells are subjected to further stress, yet some are able to survive and go on to cause relapse and metastasis. This is thought to be due to the presence of cancer stem cells, which are drug and radiation resistant.
Dr Melanie McConnell's Cell Survival Group has established various methodologies to allow identification of cancer stem cells and to characterise their function. They are using different cancer models to study the different properties of cancer stem cells self-renewal and resistance to radiation and chemotherapy using glioblastoma multiforme (GBM) cells; drug resistance in melanoma cells; and metastasis using breast cancer cells.
They have used stem cell culture, stem cell gene markers and drug resistance to identify a population of cells in GBM tumours that are highly tumourigenic and potentially immune suppressive. Neurosurgeon and Malaghan Clinical Research Fellow Mr Martin Hunn has shown that these cells can be recognised by the immune system and protect against tumour development.
Using dendritic cell immunisation to sensitise malignant glioma to chemotherapy
Contributors: Mr Martin Hunn, Kathryn Farrand, Kate Broadley, Dr Melanie McConnell, Dr Ian Hermans
One of the long term aims of the Vaccine Research Group is to develop effective and safe immunotherapies for high grade glioma (brain cancer). Complementing the phase I GBM clinical trial is a basic research programme involving Mr Martin Hunn that is investigating the possibility of directing anti-tumour immune responses specifically against GBM.
Current work is focused on developing a murine model of glioma in which to assess the efficacy and safety of vaccination strategies directed at drug-resistant tumour stem cells, to support the translation of this novel immunotherapy into clinical trial. Mr Hunn has shown that the GBM cells can grow as detached 'neurospheres' in appropriate culture media and that these spheres show increased expression of stem cell-related genes and initiate tumours earlier compared to parental tumour cells.
Mr Hunn will also undertake an in vitro assessment of the immune responses of patients with recurrent GBM who are being treated with the dendritic cell vaccine in the phase I clinical trial.
Immunotherapeutic targeting of melanoma stem cells
Contributors: Carole Grasso, Kate Broadley, Prof Mike Berridge, Dr Melanie McConnell, collaborating with Prof Jonathan Cebon (Ludwig Institute, Australia)
As part of a Melanoma Research Alliance-funded collaborative international programme aimed at using immunotherapy to target melanoma stem cells, Prof Mike Berridge, Dr Melanie McConnell and colleagues have explored the role of the putative tumour stem cell surface marker, CD133, in defining tumour-initiating (stem-like) cells in primary human metastatic melanomas.
The tumour-forming capabilities of two distinct populations of malignant melanoma cells, CD133+ and CD133-, were determined by serial passage in NOD/SCID immunocompromised mice. Unexpectedly both populations of cells were shown to initiate and sustain tumour growth with similar frequency, suggesting that CD133 is not a defining marker of stem cells for human malignant melanoma. CD133 negative cells were shown to express CD133 mRNA and intracellular protein, suggesting a failure of exocytosis independent of tumour-forming ability.
Current research is focused on searching for other potential melanoma stem cell markers.
Unleashing the power of the immune system on metastatic breast cancer
Contributors: Dr Melanie McConnell, Dr Troels Petersen, Dr Heli Matilainen, Ching-Wen Tang, Prof Mike Berridge
The Malaghan Institute's breast cancer programme, supported by BCRT, aims to develop functional vaccination strategies that induce a patient's immune cells to seek out and destroy the cells responsible for the initiation and spread of tumours. During the first year of this project a preclinical model of metastatic breast cancer has been established.
Research has also been undertaken to investigate the tumour-forming ability of cells grown under conditions that generate tumourspheres, cell clusters that in other tumour models exhibit cancer stem cell-like properties. Surprisingly, cells from breast cancer tumourspheres did not express stem cell-like gene expression markers and did not produce more aggressive tumours. Furthermore, cells from tumourspheres showed lower lung metastases, suggesting they are not stem cell-like. This led researchers to focus on the metastatic cells in the lungs of tumour-bearing mice and to use these cells in vaccination approaches.
An important outcome of this work has been the demonstration that breast cancer cells are immunogenic and generation of immune responses can protect against tumour growth and metastasis.
Sirtuins, stress and survival: A problem in anti-tumour therapy
Contributors: Susanna Brow, Kate Broadley, Dr Patries Herst, Dr Melanie McConnell
A fundamental aspect of cancer cell survival is the ability of cancer cells to change the metabolic pathways to cope with cellular stress. Understanding the survival mechanisms is key to designing effective anti-tumour therapeutics.
The sirtuin family (SIRT1-SIRT7) are NAD+-dependent enzymes with deacetylase activity, ADP-ribosyl transferase activity, or both. Based on NAD+- dependence, SIRT1 in particular has been postulated to be a metabolic sensor, relaying information on the metabolic status of the cell to the regulators of gene expression.
SIRT1 inhibition has the potential to bring specificity to cancer treatment, if in fact normal cells are less reliant on SIRT1-mediated survival pathways. In particular, where a conventional approach such as chemotherapy causes a stress response and induces survival pathways in the target cell, combining SIRT1 inhibition with that approach will potentially allow greater efficacy of cancer cell drug targeting.
The Cell Survival Group is investigating whether SIRT1 inhibition reduces cancer cell survival when combined with cytotoxic drugs, radiation or oxidative stress.
SIRT1 and stress responses in MND
Contributors: Susanna Brow, Dr Melanie McConnell
A new research programme, supported by the Motor Neurone Disease Association of NZ and the estates of Ellen, Sinclair, Barbara and Alison Wallace, has recently been initiated at the Malaghan Institute to identify specific targets of the stress response protein SIRT1 that are relevant to the survival of neurons in individuals with motor neurone disease (MND).
The ability to cope with stress is a fundamental aspect of cell survival. Stresses such as protein misfolding, oxidative stress, inflammation and dysfunctional mitochondrial metabolism occur normally during the aging of a cell, but are abnormally accelerated in MND.
SIRT1 is a key mediator of stress responses and has been shown to be upregulated in neurons. However little is known about its expression in neighbouring astrocytes, which play a critical role in signalling to neurons to keep them alive.
Dr Melanie McConnell's Cell Survival Group is addressing this question by treating normal astrocyte cells with stresses that induce a MND phenotype, before and after SIRT1 activation. Careful examination of the precise effects of SIRT1 activation in these cells will aid in the development of approaches to reduce or prevent neurodegeneration.
Herst PM, Broadley KW, Harper JL, McConnell MJ (2012) Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radic Biol Med, 52:1486-93
Hunn MK, Farrand KJ, Broadley KW, Weinkove R, Ferguson P, Miller RJ, Field CS, Petersen T, McConnell MJ, Hermans IF Vaccination wtih irradiated tumor cells pulsed with an adjuvant that stimulates NKT cells is an effective treatment for glioma. Clin Cancer Res, 2012 Nov 12 [Epub ahead of print]
Klionsky DJ et al (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 8:445-544
Matilainen H, Yu XW, Tang CW, Berridge MV, McConnell MJ (2012) Sphere formation reverses the metastatic and cancer stem cell phenotype of the murine mammary tumour 4T1, independently of the putative cancer stem cell marker Sca-1. Cancer Lett, 323:20-8
Robinson M, McConnell MJ, Le Gros G How epigenetic imprinting contributes to stabilizing the Th2 phenotype. Immunol Cell Biol, 2012 Sep 25 [Epub ahead of print]
Broadley KW, Hunn MK, Farrand KJ, Price KM, Grasso C, Miller RJ, Hermans IF, McConnell MJ (2011) Side population is not necessary or sufficient for a cancer stem cell phenotype in glioblastoma multiforme. Stem Cells, 29:452-61
Broadley K, Larsen L, Herst PM, Smith RA, Berridge MV, McConnell MJ (2011) The novel phloroglucinol PMT7 kills glycolytic cancer cells by blocking autophagy and sensitizing to nutrient stress. J Cell Biochem, 112:1869-79
Berkofsky-Fessler W, Buzzai M, Kim M, Fruchtman S, Najfeld V, Min DJ, Costa F, Bischoff J, Soares M, McConnell M, Zhang W, Levine R, Gilliland DG, Carogero R, Licht JD (2010) Transcriptional profiling of polycythemia vera identifies gene expression patterns both dependent and independent from the action of JAK2V617F. Clin Cancer Res, 16:4339-52
Osmond TL, Broadley KW, McConnell MJ (2010) Glioblastoma cells negative for the anti-CD133 antibody AC133 express a truncated variant of the CD133 protein. Int J Mol Med, 25:883-8
Rice KL, Hormaeche I, Doulatov S, Flatow JM, Grimwade D, Mills KI, Leiva M, Ablain J, Ambardekar C, McConnell MJ, Dick JE, Licht JD (2009) Comprehensive genomic screens identify a role for PLZF-RARa as a positive regulator of cell proliferation via direct Regulation of c-MYC. Blood, 114:5499-511
Fandy TE, Herman JG, Kerns P, Jiemjit A, Sugar EA, Choi S, Yang AS, Aucott T, Dauses T, Odchimar-Reissig R, Licht JD, McConnell MJ, Nasrallah C, Kim MKH, Zhang W, Sun Y, Murgo A, Espinoza-Delgado I, Oteiza K, Owoeye I, Silverman LR, Gore SD, Carraway H (2009) Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood, 114:2764-73
Xu D, Holko M, Sadler AJ, Scott B, Higashiyama S, Berkofsky-Fessler W, McConnell MJ, Paolo Pandolfi P, Licht JD, Williams BRG (2009) Promyelocytic leukemia zinc finger protein regulates interferon-mediated antiviral innate immunity. Immunity, 30:802-16
van Panhuys N, Le Gros G, McConnell MJ (2008) Epigenetic regulation of Th2 cytokine expression in atopic diseases. Tissue Antigens, 72:91-7
Xue J, Zhou D, Yao H, Gavrialov O, McConnell MJ, Gelb BD, Haddad GG (2007) Novel functional interaction between Na /H exchanger 1 and tyrosine phosphatase SHP-2. Am J Physiol: Regulatory, Comparative and Integrative Physiology
McConnell MJ, Licht JD (2007) The PLZF gene of t(11;17)-associated APL. Curr Topics Microbiol Immunol, 313:31-48
Guidez F, Howell L, Isalan M, Cebrat M, Alani RM, Ivins S, Hormaeche I, McConnell MJ, Pierce S, Cole PA, Licht J, Zelent A (2005) Histone acetyltransferase activity of p300 is required for transcriptional repression by the promyelocytic leukemia zinc finger protein. Mol Cell Biol, 13:5552-66
Takahashi S, McConnell MJ, Harigae H, Kaku M, Sasaki T, Melnick AM, Licht JD (2004) The Flt3 internal tandem duplication mutant inhibits the function of transcriptional repressors by blocking interactions with SMRT. Blood, 103:4650-8
McConnell MJ, Chevallier N, Berkofsky-Fessler W, Giltnane JM, Malani RB, Staudt LM, Licht JD (2003) Growth suppression by acute promyelocytic leukemia-associated protein PLZF is mediated by repression of c-myc expression. Mol Cell Biol, 24:9375-88
Topisirovic I, Guzman ML, McConnell MJ, Licht JD, Culjkovic B, Neering SJ, Jordan CT, Borden KL (2003) Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis. Mol Cell Biol, 24:8992-9002
Dai MS, Chevallier N, Stone S, Heinrich MC, McConnell M, Reuter T, Broxmeyer HE, Licht JD, Lu L, Hoatlin ME (2002) The effects of the Fanconi anemia zinc finger (FAZF) on cell cycle, apoptosis, and proliferation are differentiation stage-specific. J Biol Chem, 277:26327-34
Ward JO*, McConnell MJ*, Carlile GW, Pandolfi PP, Licht JD, Freedman LP (2001) The acute promyelocytic leukemia-associated protein, promyelocytic leukemia zinc finger, regulates 1,25-dihydroxyvitamin D(3)-induced monocytic differentiation of U937 cells through a physical interaction with vitamin D(3) receptor. Blood, 98:3290-300
Melnick A, Carlile GW, McConnell MJ, Polinger A, Hiebert SW, Licht JD (2000) AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein. Blood, 96:3939-47
McConnell MJ, Cunliffe HE, Chua LJ, Ward TA, Eccles MR (1997) Differential regulation of the human Wilms tumour suppressor gene (WT1) promoter by two isoforms of PAX2. Oncogene, 14:2689-700