Postdoctoral Researcher in RNA Translation and Anti-Cancer Immunity

**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 inhibition



2) Organoid tissue culture with the patient’s own immune cells



We 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.



We are looking for an enthusiastic postdoctoral researcher who will be
involved in every aspect of the project taking on responsibility for setting
up and applying the necessary molecular biology tools. The expertise in the
wet lab execution of Ribo-seq and proteomics is a significant asset for the
position. The experiments will be performed in cell line models and organoids.
The appointee will be expected to work closely with a number of collaborating
groups in UK (Harveer Dev, Cambridge University and Mills, Oxford University)
and in Finland/Norway (Itkonen, University of Oslo and University of
Helsinki). The appointee will be based principally in Oxford.





**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**



If you would like to discuss this role, please contact Professor Ian Mills:
ian.mills@nds.ox.ac.uk and Dr Harri Itkonen: harri.itkonen@helsinki.fi








Applications for this vacancy are to be made online. You will be required to
upload a supporting statement of maximally two pages setting out how you meet
the selection criteria, curriculum vitae that includes potential peer reviewed
publications, and the names and contact details of two referees as part of
your online application. Please quote reference NDSA951 on all correspondence.





Only applications received before noon on the 10th January 2025 can be
considered.





Interviews will be held on the 22nd January 2025.





**Committed to equality and valuing diversity**