Postdoctoral Researcher in RNA Translation and Anti-Cancer Immunity

Radiation Research Institute/ORCRB, Old Road Campus, Roosevelt Drive, Headington, Oxford, OX3 7DQ Grade 7RS: £38,674 - £46,913 (including the Oxford University Weighting of £1,500 per annum) Location: Radiation Research Institute/ORCRB Contract type: Fixed term for 24 months with the possibility of extension Hours: Full-time About the role and project Prostate cancer (PC) is the most common male cancer in the United Kingdom and more effective treatments are needed to control the late-stage disease. In the lethal disease, termed castration-resistant PC (CRPC), cancer cells sustain the pro-proliferative gene expression program despite of the presence of anti-androgens by activating other oncogenes, particularly the MYC transcription factor. This gene expression program is ultimately dependent on cyclin-dependent kinase 9 (CDK9), and CDK9 inhibitors are currently in clinical trials for solid tumors. All cells depend on CDK9 to sustain gene expression, and it has not been comprehensively established why cancer cells are sensitive against the CDK9 targeting drugs. Our preliminary data show that CDK9 inhibition activates innate immune response through viral mimicry in PC cells. In MYC over-expressing prostate cancer cells, CDK9 inhibition leads to gross accumulation of mis-spliced RNA. Double-stranded RNA (dsRNA)-activated kinase can recognize these mis-spliced RNAs, and we show that the activity of this kinase is required for the CDK9 inhibitor-induced anti-proliferative effects. CDK9 inhibition stimulates translation of specific proteins, and we show that depletion of CDK9 activity leads to excessive secretion of immunogenic cytokines. However, we do not yet know the extent to which protein biosynthetic machinery is remodelled, and if the increased secretion of the cytokines can potentiate the cytotoxic effects of the immune cells.In this project, we have two independent aims:1) Remodelling of the translation landscape in response to CDK9 inhibition2) Organoid tissue culture with the patient’s own immune cellsWe will rely on nascent profiling of ribosome and patient-derived models to establish how CDK9 inhibition remodels the proteome and the transcriptional activity in cancer and immune cells. Using nascent Ribo-seq, nascent chain proteomics and total proteomics, we will describe how CDK9 inhibition changes PC cells ability to maintain homeostasis of the proteome. We will treat patient-derived organoids cultured in the presence of the matched peripheral blood mononuclear cells with CDK9 inhibitors and perform scSLAM-seq to establish how depletion of the major transcriptional kinase alters tumor and immune cells’ transcriptomes. These experiments are innovative but rely on the core expertise of our laboratories. About you You will hold a PhD/DPhil in molecular biology, oncology, immunology, or a related biomedical science field. Previous research experience and specialist knowledge in cancer immunology, RNA translation, or ribosome-profiling would be desirable. You will be experienced in cellular and molecular biology techniques with mammalian cell culture. You will have excellent verbal and written communication skills, and ability to communicate results clearly in presentations, manuscripts, and grant reports.This full-time position is available for a 24-month period in the first instance. Application Process