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Campbell Lab
Moray Campbell, PhDDepartment of Pharmacology & Therapeutics
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY USA 14263
Tel: 716-845-3037
Fax: 716-845-8857
E-mail: moray.campbell@roswellpark.org
Education
PhD, University of Kent, UK
Post Doctoral, Cedars Sinai Medical Centre, UCLA Medical School, USA
Research Interests
This nuclear receptor super-family of transcription factors operates as a network to co-ordinate transcriptional programs in response to a diverse input of lipophillic molecules, including steroidal hormones, dietary derived molecules and xenobiotics. Specifically, ongoing research aims to model this network behaviour and establish mechanisms by which it becomes corrupted in malignancy.
Current Research
In common with the sites of many solid tumours and leukaemia, the prostate is a self-renewing structure with identified prostate stem cells. A diverse range of signalling processes controls the rate and symmetry of stem cell division and subsequent progenitor mitosis. Distortions to these processes account for the heterogeneity of disease progression and clinical outcome, based on differences between the specific tumour-initiating cell type and its signal transduction capacity. Insights into prostate cancer progression will most likely arise from understanding the signals that control the proliferation and differentiation capacity of stem and progenitor cells. Among these regulation processes, multiple members of the nuclear receptor super-family function as an important signalling conduit in the prostate.
Two themes are being addressed:
- Developing a network view of the nuclear receptor super-family. A central goal of this modelling process is to move away from exclusive views of individual receptor actions as either inhibiting or promoting cell proliferation, towards an integrated contextual one allowing for flexible transcriptional outputs. Such flexibility depends on expression of co-factors, receptor ligand availability and the broader cell context. Systems biology modelling tools are being utilised to develop models for individual and combined nuclear receptor actions that account for emergent network behaviour.
- Revealing and exploiting the critical control nodes in the nuclear receptor network as novel therapeutic targets. Findings to date have revealed elevated co-repressor mRNA and protein, for example in prostate cancer primary cultures and cell lines, compared to non-malignant counterparts. The effect of this is to suppress the transcriptional plasticity of the nuclear receptor network, with the actions of individual receptors becoming selective and inflexible. Targeting the co-repressor complex with either shRNA approaches or minimal doses of HDAC inhibitors resulted in unique patterns of re-expressed gene targets and restored the antipoliferative effects of multiple receptors (e.g. VDR, PPARs, and RAR). These studies further validate the concept that sub-transcriptomes are selectively repressed in cancer cell as a result of distorted co-repressor function. Nuclear receptor co-repressors act as nodal control points of multiple members of the nuclear receptor network. Findings to date in prostate, breast and bladder cancer cells support the concept that distinct co-repressor complexes attenuate the anti-mitotic actions of a sub-set of nuclear receptors selectively. In turn elevated co-repressor expression and function forms a specific lesion to be targeted selectively with epigenetic therapies. We have proposed, and are currently investigating to what extent, this occurs at the level of sensing and mediating specific histone modifications.
Selected Publications
