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Val Macaulay

Igf1

The aim of our research is to understand the contribution of insulin-like growth factor (IGF) signalling to cancer biology, and exploit this information in the management of patients with cancer.  Production of IGF-1 from the liver is regulated by growth hormone, and people with congenital deficiencies of growth hormone or IGF-1 are strongly protected from developing cancer.  Conversely, people with high blood levels of IGF-1 are at increased risk of developing cancer.  IGFs binds to type 1 IGF receptors (IGF-1Rs) that are expressed on the cell surface, promoting cancer cell growth and spread, and resistance to killing by cancer drugs and radiotherapy. Therefore, blocking IGF actions offers the potential to suppress cancer development, and increase sensitivity to anti-cancer treatments.

We have shown that IGF-1Rs are up-regulated in prostate and renal cancers, and detectable in advanced primary tumours and metastatic disease.  We also demonstrated that IGF-1R undergoes IGF-dependent import into the nucleus of human tumour cells. Nuclear IGF-1R associates with adverse prognosis in renal cancer and advanced stage in prostate cancer, suggesting a link with aggressive tumour behaviour. Supporting this concept, our ChIP-seq data reveal ligand-dependent recruitment of nuclear IGF-1R to regulatory regions of genes that promote cancer cell survival and motility.  

The two main aims of current work are to investigate the function of nuclear IGF-1R, and develop approaches to exploit the IGF axis as a target for therapy.  We aim to identify factors that influence sensitivity to drugs that block the IGFs, and test IGF inhibition as a route to sensitise cancers to radiation and other forms of cancer treatment. We find that IGF-1R expression associates with adverse outcome after radiotherapy for prostate cancer, and IGF-1R inhibition delays repair of DNA double-strand breaks, apparently independent of its well-known ability to regulate apoptosis induction.  Understanding the basis of this effect may enable effective exploitation of this approach in the clinic. 

IGF 1

Figure 1: Nuclear IGF-1R binds regulatory regions of DNA, promoting expression of genes that drive tumour cell survival and migration. A. Membrane and nuclear IGF-1R in human prostate cancer cells. B. ChIP-seq-identifies limited number of IGF-1R binding sites that cluster near transcription start sites. C. IGF-1R binding sites (red bars) within JUN and FAM21A promoters, coincident with RNAPol2 and H3K4me1 peaks. Graphs below: ChIP-qPCR confirms IGF-dependent IGF-1R recruitment to JUN and FAM21A promoters. D. IGF-1R is detectable on JUN and FAM21A promoters in fresh samples of prostate cancer that contain nuclear IGF-1R. E. Nuclear IGF-1R binds to DNA and interacts with transcriptional regulators including RNAPol2 and GATA2, inducing expression of genes that promote tumour cell survival and migration.

IGF 2

Figure 2: IGF-1R as a mediator of radioresistance. A-C. IGF-1R inhibition (IGF-1Ri): A, blocks IGF-induced IGF-1R activation; B, enhances radiosensitivity of human prostate cancer cells; C, delays resolution of radiation-induced DNA damage marked here by gH2AX foci. D. In men treated with radical radiotherapy for prostate cancer (n=136), high total IGF-1R associates with risk of total and metastatic recurrence, and internalised (nuclear plus cytoplasmic) IGF-1R with biochemical recurrence. The latter category includes men experiencing recurrence within the radiation field, indicating clinical radioresistance.

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