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Postdoc Appreciation Week - MCRC Postdoc Publications

Postdoc Appreciation Week 2020 (21st – 25th September) is an annual event designed to highlight the global achievements and contributions of postdocs (research fellows, research associates, bioinformatic officers etc.). Originating with the National Postdoc Association in the USA (National Postdoc Appreciation Week), the University of Manchester has since won the 2019 Elsevier ‘Best New Event’ Award for Postdoc Appreciation Week and is now part of the first UK/ROI-wide consortium celebrating postdocs across UK and Irish Universities.
 
Recognising postdoctoral successes is paramount; they not only contribute world-leading research to our field but have been found to be instrumental in training the next generation of researchers.
 
Particularly given the current climate of COVID-19, the Manchester Cancer Research Centre wishes to recognise our postdocs’ 2019–20 outstanding contributions; we inevitably won’t have captured all successes - if you are a current postdoc with achievements we could highlight, we’d love for you to get in touch with us at MCRCtraining@manchester.ac.uk.

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Breast Cancer Research

 

Led by Professor Rob Clarke, the Manchester Breast Centre's mission is to create a world-class centre for basic and translational breast cancer research, leading to effective detection and treatment of women at risk, and ultimately elimination of the disease.
 
2019–20 peer-reviewed publications from postdocs include Dr Rachel Eyre, Dr Angélica Santiago-Gómez and Dr Bruno Simões’ co-authorship of multiple, cutting-edge articles, including:

Dr Hannah Harrison has contributed to multiple peer-reviewed papers, including as co-first author of ‘A role for CBFβ in maintaining the metastatic phenotype of breast cancer cells’ and a co-author of ‘Hypoxia‐induced secretion stimulates breast cancer stem cell regulatory signalling pathways’.

Cancer Biomarker Centre


Cancer Precision Medicine at its foundation requires biomarker-informed patient management to maximise benefit and reduce harm. Biomarkers that emanate from discoveries in both basic science and reverse translation from the clinical observations are needed for all aspects of a cancer patient’s ‘journey’, from the pre-disposition and early detection of cancer through to best care in advanced disease.

 

The Cancer Research UK Manchester Institute Cancer Biomarker Centre (pictured), led by Professor Caroline Dive CBE (CRUK MI Deputy Director) has more than 100 members of staff within laboratories for tumour biology, biomarker discovery and preclinical pharmacology research alongside regulated laboratories for biomarker assay validation and qualification within clinical trials to Good Clinical Practice standards supporting clinical decision-making. Critically, they have established strong links to The Christie NHS Foundation Trust, the largest comprehensive, dedicated and research active cancer hospital in Western Europe receiving over 15,000 new cancer patients each year and the hub of an extensive developed cancer delivery network across 3.2 million people.
 
Postdoctoral scientist, Dr Francesca Chemi was first author on ‘Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse’, published in Nature Medicine. Study of CTCs from 100 NSCLC patients shows patients with very high CTC number isolated during surgery highly likely to relapse.  Remarkably, Dr Chemi and co-authors showed that the CTCs contained mutations more in common with the secondary tumour than the primary tumour from which they originated, indicating that CTCs are indeed the source of metastasis.

Postdoctoral scientist, Dr Sumitra Mohan was first author on ‘Analysis of circulating cell-free DNA identifies KRAS copy number gain and mutation as a novel prognostic marker in pancreatic cancer’.  In multivariable Cox Regression analysis, they showed for the first time that patients with KRAS copy number gain and KRAS mutation have significantly worse outcomes, suggesting that this may be linked to PDAC progression. The simple cfDNA assay they describe will enable determination of the presence of KRAS copy number gain and KRASmutations in larger studies and clinical trials.

Dr Mohan also first-authored ‘Profiling of circulating free DNA using targeted and genome wide sequencing in patients with small cell lung cancer’, which explored utility of cfDNA analysis for disease monitoring and CNA profiles and showed dynamic changes through therapy to disease relapse. The liquid biopsy approaches reported here are promising and may have potential to become a routine patient-monitoring tool in the clinic.

Cancer Prevention and Early Detection

Our Cancer Prevention and Early Detection theme aims to reduce the inequalities associated with cancer prevention and early detection by identifying those populations in Greater Manchester at highest cancer risk; establish and validate rules to predict cancer risk; develop personalised approaches to select the most appropriate preventive therapy and/or lifestyle interventions and reduce the number of patients diagnosed with late-stage cancers in Greater Manchester, by improving and developing new early detection methods. We are part of the International Alliance for Cancer Early Detection (ACED), a new £55 million partnership between Cancer Research UK, the Canary Center at Stanford University, the University of Cambridge, the Knight Cancer Institute at OHSU, University College London and the University of Manchester.
 
Professor Andrew Renehan and Professor Emma Crosbie wished to highlight Dr Ellena Badrick’s first-authored publication ‘Top ten research priorities for detecting cancer early’. Dr Badrick’s work on the James Lind Alliance PSP Top Ten Priorities in Cancer Early Detection research (read more here) was featured in the MCRC Annual Report and won first prize at the Greater Manchester Cancer Conference 2019.

Cell Signalling

The small GTPase RAC regulates many normal cellular processes, but it can also enhance the formation and progression of cancers via mutation, overexpression or altered regulation. The aim of the Cell Signalling laboratory at the CRUK Manchester Institute, led by Professor Angeliki Malliri, is to find RAC-dependent targets, which are specific to tumour cells, and hence provide new therapeutic avenues without disrupting the necessary physiological roles of RAC in healthy cells.
 
Dr Andrew Porter, postdoctoral research fellow, was first author on ‘The interaction between CASK and the tumour suppressor Dlg1 regulates mitotic spindle orientation in mammalian epithelia’. Oriented cell divisions are important for the formation of normal epithelial structures. Dlg1, a tumour suppressor, is required for mitotic spindle orientation in Drosophila epithelia and chick neuroepithelia, but how Dlg1 is localised to the membrane and its importance in mammalian epithelia are unknown. Dr Porter and co-authors showed that Dlg1 is required in non-transformed mammalian epithelial cells for oriented cell divisions and normal lumen formation. They further demonstrated that the MAGUK protein CASK, a membrane-associated scaffold, is the factor responsible for Dlg1 membrane localisation during spindle orientation, thereby identifying a new cellular function for CASK.

Chronic Myelomonocytic Leukaemia (CMML)

Epigenetics of Haematopoiesis group co-led by Dr Kiran Batta and Dr Daniel Wiseman is core-funded by The Oglesby Charitable Trust and is highly integrated with a tertiary referral clinical practice based at the adjacent Christie Hospital. They work closely with Professor Tim Somervaille’s Leukaemia Biology Group, thereby providing a stimulating collaborative environment with access to a diverse range of expertise and resources. Professor Somervaille is a group leader at the CRUK Manchester Institute.
 
Dr Wiseman and Dr Batta’s postdoc, Dr Arundhati Dongre has co-authored ‘Chronic myelomonocytic leukaemia stem cell transcriptomes anticipate disease morphology and outcome’, which provides novel insights into the CMML stem cell compartment, revealing an unexpected degree of heterogeneity and demonstrating that CMML stem cell transcriptomes anticipate disease morphology, and therefore outcome. 

Gynaecological Oncology

The Gynaecological Oncology group is based on the Research Floor at Saint Mary’s Hospital, within the Department of Obstetrics and Gynaecology. Saint Mary’s is part of the Manchester University NHS Foundation Trust (MFT), formed in 2017 following the merger of Central Manchester University Hospitals NHS Foundation Trust (CMFT) and University Hospital of South Manchester NHS Foundation Trust (UHSM).

The Gynaecological Oncology group’s collaboration between scientists and clinicians has established Manchester as a leading centre of human papillomavirus (HPV) research both nationally and internationally. The group's current research portfolio includes external funding in excess of £3.5 million, with a particular emphasis on screening, prevention and early detection of gynaecological cancers.
 
Professor Emma Crosbie was keen to recognise the successes of the NIHR Clinical Lecturers within her group. Dr Sarah Kitson (pictured) won the Most Outstanding Output during her PhD on Gynaecological Oncology at the University of Manchester, Faculty of Biology Medicine and Health’s Doctoral Academy Awards 2019. She has recently first-authored ‘BRCA1 and BRCA2 pathogenic variant carriers and endometrial cancer risk: A cohort study' and ‘PRE-surgical Metformin In Uterine Malignancy (PREMIUM): a multi-center, randomized double-blind, placebo-controlled phase 3 trial’.

Dr Vanitha Sivalingam, an NIHR clinical lecturer with Professor Crosbie, was co-author on the latter paper.

Leukaemia Biology

Human acute myeloid leukaemias (AMLs) are heterogeneous with respect to the function of the cells that make up the disease. A minority of the cells are so called leukaemia stem cells (LSCs) which have the ability to self-renew for an extended, if not indefinite, period, while maintaining and expanding the disease. Professor Tim Somervaille’s  Leukaemia Biology research group is part of the Cancer Research UK Manchester Institute (CRUK MI); they aim to further the understanding of the biology of human LSCs, in order to identify genes and cellular pathways that are critical for their function and which could be targeted by novel therapies. CRUK MI supports a number of investigative programmes, spanning both basic and translational cancer research.
 
Dr Bettina Wingelhofer, a postdoctoral fellow with Professor Somervaille, based at CRUK MI has co-authored ‘Pre-clinical activity of combined LSD1 and mTORC1 inhibition in MLL-translocated acute myeloid leukaemia’. The first author was Dr Gauri Deb, a former CRUK MI postdoctoral scientist. Using a genome-wide CRIPSR-Cas9 knockout screen, they were able to show that dual mTORC1 and LSD1 inhibition represents a candidate combination approach for enhanced differentiation in MLL-translocated acute myeloid leukaemia, which could be evaluated in early phase clinical trials.

Mitosis and Cancer Pharmacology

Professor Stephen Taylor, Head of the Division of Cancer Sciences, and The Taylor Lab (pictured below), wanted to recognise and celebrate the achievements of all of his research staff.

Facilitated by their close proximity to The Christie, the Taylor Lab collects samples from patients with chemo-naïve and relapsed ovarian cancer, either as solid biopsies or ascites. They have established a workflow to generate ex vivo cultures of highly purified tumour cells, unfettered by contaminating, genetically normal stromal cells and the microenvironment, with extensive proliferative potential.

2019–20 publications by Dr Anthony Tighe, Dr Louisa Nelson, Sam Littler, Dr Cam Coulson-Gilmer and Dr Beth Barnes include:

 

Molecular Oncology

As members of the CRUK MI community, the Molecular Oncology research group, led by Professor Richard Marais (CRUK MI Director), aims to expand knowledge of the basic biology underlying tumorigenesis in melanoma, breast and prostate cancer and translate this to patient benefit. Working in a multidisciplinary team composed of cell and molecular biologists as well as clinicians ensures that their discoveries are exploited in the fields of early detection of disease, personalised medicine and the development of novel therapeutic approaches.
 
Postdoctoral scientist, Dr Lucas Trucco was first author on ‘Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma’. This paper classifies melanomas by mutation signatures and identifies ten recurrently mutated UVR signature genes that predict patient survival. They validate these findings in primary human melanomas; in mice they show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.

Postdoctoral fellow, Dr Elena Galvani, now working as a senior scientist for AstraZeneca, was first author on ‘Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma’.
 
Dr Sara Valpione, clinical fellow, first-authored ‘Immune-awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy’. This paper analysed peripheral T cell populations after one cycle of CPI and identified a dynamic awakening of the immune system revealed by T cell evolution in response to treatment. They found that early peripheral T cell turnover and TCR repertoire dynamics identified which patients would respond to treatment. Additionally, the expansion of a subset of immune-effector peripheral T cells they called TIE cells correlated with response. These events are prognostic and occur within 3 weeks of starting immunotherapy, raising the potential for monitoring patient responses using minimally invasive liquid biopsies.

 

Radiotherapy Related Research (RRR)

The Radiotherapy Related Research (RRR) Group was established in 2007 by the Manchester Cancer Research Centre (MCRC), to develop an internationally leading multi-disciplinary research group of University of Manchester academics and Christie researchers. Their radiotherapy research now has a particular focus on image-guided radiotherapy, proton therapy, radiobiology, imaging, theragnostics and radiotherapy-immunotherapy combinations. Much of this is enabled by cutting-edge facilities at The Christie that include Stereotactic Ablative Body Radiotherapy, an MR-Linac and a Proton Therapy Centre. We are part of CRUK RadNet, network of centres of excellence and state-of-the-art facilities working with the research community to tackle the major challenges in radiobiology and radiation oncology, with £56 million investment over 5 years.
 
The PRECISE (Proton research at The Christie and the University’s Division of Cancer Sciences) group is led by Professor Karen Kirkby. With achievements highlighted by Professor Kirkby and Dr Michael Merchant, the Proton Beam Therapy research room has seen a number of the PRECISE group postdocs, namely Dr Nicholas Henthorn, Dr John Warmenhoven and Dr Elham Santina getting the hypoxia end station up and working; the team have made huge efforts and have already conducted their first test biology experiment. 
 
Dr John Warmenhoven, research associate, first-authored ‘Insights into the Non-Homologous End Joining Pathway and Double Strand Break End Mobility Provided by Mechanistic In Silico Modelling’ with co-author Dr Amy Chadwick, research associate et al. This paper included Sam Ingram and Marios Sotiropoulos, PhD students from this lab. Dr Warmenhoven co-authored ‘Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway’. Dr Chadwick first-authored ‘Proton Beam Therapy – perspectives on the National Health Service England clinical service and research programme’. Dr Nicholas Henthornwas first author on ‘Mapping the Future of Particle Radiobiology in Europe: The INSPIRE Project’ and co-authored ‘A parameter sensitivity study for simulating DNA damage after proton irradiation using TOPAS-nBio’, amongst other publications.
 

Dr Azadeh Abravan is a research associate in Professor Marcel van Herk’s group. Dr Abravan’s abstract was awarded the highest scoring abstract under physics track at
ESTRO 2019 and has now been published as the first-authored paper ‘Radiotherapy-related lymphopenia affects overall survival in patients with lung cancer’ in Journal of Thoracic Oncology. Her research was also highlighted in a press release by The Christie NHS Foundation Trust.

Translational Oncogenomics

With an estimated 1.3 million new cases identified worldwide in 2018, prostate cancer is the most frequently diagnosed male cancer in the Western world, and in the UK, there are approximately 11,700 prostate cancer deaths per year. The Translational Oncogenomics group, led by Professor Rob Bristow at the Cancer Research UK Manchester Institute (CRUK MI) investigates the mechanisms by which DNA repair gene dysfunction leads to genetic instability and aggression within prostate cancer.
 
Dr Richard Rebello (pictured), postdoctoral scientist, first-authored ‘Intermediate Risk Prostate Cancer: Disease Heterogeneity Linked to Measurable Biological Features’, which was published in Clinical Oncology. Localised prostate cancer (PCa) remains a disease setting where absolute prognostication is difficult, as features that indicate upfront clinical aggression may not be apparent. An active area of this research is identifying prostate tumours that will ultimately evade therapy or acquire treatment resistance and these may have upfront aggressive features which precede histopathology.
 
Dr Rebello also co-authored multiple papers this year, including ‘Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment’ and ‘CRISP3 expression drives prostate cancer invasion and progression’.

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As part of Postdoc Appreciation Week, we will also be highlighting ‘MCRC Postdoc Grants and Awards, Presentations, Public Engagement and Media’ later this week. Any queries or successes to highlight can be directed to MCRCtraining@manchester.ac.uk.

 

 


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Georgina is the MBPhD Administrator and Recruitment and Training Officer

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