NIHRDataInsights/HRCSData huggingface dataset:
Title: The regulation of Wilms' tumour 1 by phospholipid
Funder: Medical Research Council

Abstract: WT1 can act as either a tumour suppressor or oncogene in several cancers, but how these activities are controlled is not clear. We identified BASP1 as a critical regulator of WT1. WT1 and BASP1 form a complex that represses transcription of WT1 target genes. Our central hypothesis is that BASP1 acts as a switch to convert WT1 from a transcriptional activator to a transcriptional repressor, and that this mechanism is critical in directing its tumour suppressor and oncogenic activities. Our recent findings have revealed that the N-terminal myristoylation of BASP1 is required to elicit transcriptional repression at WT1 target genes. Moreover, myristoylated BASP1 binds to nuclear phosphatidylinositol 4, 5-bisphosphate (PIP2), which stimulates the recruitment of HDAC1 to the promoter to mediate transcriptional repression. Our findings have uncovered a novel role for myristoylation in transcription, and a critical function for PIP2 in gene-specific transcriptional repression through the recruitment of histone deacetylase. This proposal seeks to determine the mechanisms by which the PIP2-BASP1 interaction regulates WT1 function in gene expression and cell fate. These studies will provide new insights into the mechanisms of WT1 action in development, and will also open new avenues for therapy in several major cancers. The aims are; 1. Determine the role of PIP2 in the modulation of BASP1 contacts with the chromatin remodelling and transcription machinery, and how PIP2 regulates WT1-dependent gene expression. 2. Study how BASP1-PIP2 contact is regulated by the phosphorylation of BASP1 and how this regulates WT1 function. 3. Determine the role of BASP1-PIP2 in the control of cell proliferation and differentiation using a model of kidney podocyte differentiation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;RENAL AND UROGENITAL
Title: Investigation of the role of B cells and the tolerance signature in cutaneous squamous cell carcinoma in renal transplant recipients.
Funder: Wellcome Trust

Abstract: Kidney transplant recipients (KTR) must receive long-term medication to suppress their immune system to prevent transplant rejection. This medication puts patients at a much higher risk of developing a type of skin cancer called SCC. A previous study has shown that KTR who develop SCC have an increased number of immune cells ('Treg'). Work in KTR whose transplants continue working even without immunosuppression (termed 'tolerance') has allowed identification of a 'signature' associated with this state. This signature has not been looked at in the general KTR population but implicates another type of immune cell ('Breg') in being heavily involved in tolerance. However, Breg are also involved in SCC development in animal models, but we do not know if they play a role in human SCC. Breg have been shown to stimulate Treg formation. We will recruit KTR who do and do not develop SCC in order to establish whether this is associated with the tolerance signature and increased Breg nu mbers. We will analyse blood and look for the signature, then assess Breg function in both groups. We will look at the skin cancer from KTR and patients without a transplant and compare levels of Breg around the tumours.


Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS;RENAL AND UROGENITAL
Title: Are women who have hormonal assisted reproductive therapy (ART) and children born after assisted reproductive therapy (ART) at higher risk of cancer?
Funder: Department of Health (England)

Abstract: Objectives: To investigate cancer risk in women who have had hormonal assisted reproductive therapy (ART) and Children born after ART. Design: Data will be linked from the HFEA database (recording all UK ART cycles from 1990) to: • NHS-Information Centre Medical Register (recording all cancers and deaths in UK population) • National Registry of Childhood Tumours Outcomes: Rates of women and children developing cancer after ART will be determined and compared with expected rates. Risk of specific cancers will be secondary outcomes. Anticipated Benefits: Better information on these potential risks may inform pre-treatment counselling, treatment protocols and possible surveillance programs


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Systematic investigation of the effect of chemotherapeutic agents on the ovary using ovarian follicle culture systems
Funder: Medical Research Council

Abstract: The human ovary contains a fixed supply of germ cells, oocytes, maintained within ovarian follicles. Chemotherapeutic agents are known to damage ovarian follicles, and due to the finite nature of the follicle pool, this damage is irreversible (since germ cells cannot later be regenerated, as is possible for many other damaged tissues). As a result of this damage, premature ovarian failure (POF) and hence infertility occurs in a significant number of young female cancer patients. With recent advances in cancer treatment leading to increased survival rates, the long-term adverse affects of chemotherapy on female fertility now demand attention. We propose to investigate the effect of chemotherapeutic drugs using established follicle culture techniques of which the applicants have considerable expertise in both mouse and larger mammalian species (including humans), to determine the precise sequence of events that results from exposure to the drugs, establishing which effects are direct and which are indirect, secondary consequences. This is vital, since treatment to prevent POF would need to protect against the initial, direct effect if it is to be successful. These in vitro models allow ovarian follicle material of known developmental stages to be exposed to chemotherapeutic drugs and then monitored closely. Such analysis is not possible in vivo, because of the heterogeneity of the ovarian follicle population. This heterogeneity precludes the possibility of determining the developmental stage at exposure of any follicle subsequently found to be affected. The first part of the proposal will concentrate on using well established in vitro animal models to investigate effects of five individual chemotherapeutic agents and two of the most common drug combinations used in young patients. Experiments will be undertaken to investigate germ cell survival and follicle growth, examining site and time course of apoptosis and cell proliferation. In the second half, we will examine key drugs and doses using: (a) in vitro fertilisation carried out on cultured mouse material to determine fertilisation rate and embryo viability of oocytes previously exposed to low doses of chemotherapeutic agents; and (b) culture of human ovarian material, to check that similar effects are seen in human as in mouse. By carrying out the first, detailed screen using mouse material, we can ensure optimal use of the more limited supply of human material. In a final series of experiments, we will test key findings in vivo to assess how our findings translate into a murine preclinical model.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Charting cellular changes in the human breast associated with embryogenesis, parity, age, menopause and germline mutations
Funder: Medical Research Council

Abstract: One of the biggest challenges in treating breast cancer is the heterogenous nature of the disease which is initiated by oncogenic events in a tumour initiating cells. To fully understand the contribution of the cell of origin to this heterogeneity we must first comprehensively identify the different cell types found in the breast and map how they change in response to various developmental processes. We propose here to use single cell sequencing approaches to identify and chart the differentiation dynamics of epithelial and non-epithelial breast cells during embryonic development and in response to aging, parity, lactation, menopause and germline mutations. We will use two types of single cell sequencing approaches to tackle this problem; scRNAseq and scATACseq. The scRNAseq data will allow us to identify the different types of cells found in the breast across these different developmental conditions while scATACseq will allow us to identify changes in the chromatin accessibility states of these different cell clusters thus, indicating a switch in the epigenetic identity of the cell. Therefore, if awarded, this grant will allow us to generate a comprehensive Human Breast Cell Atlas which will provide the breast cancer research community with an unparalleled resource to accelerate the discovery of novel biomarkers and mechanisms behind breast cancer development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: CRUK/13/015: SHAPE - A randomised phase III trial comparing radical hysterectomy and pelvic node dissection vs simple hysterectomy and pelvic node dissection in patients with low-risk early-stage cervical cancer: The SHAPE trial (NCIC CTG Study CX.5)
Funder: Cancer Research UK

Abstract: Cervical cancer is the second most common worldwide cause of female cancer deaths; there are approximately 493,243 cases each year with 273,505 deaths. In the U.K in 2010 there were 3500, cases and 940 deaths. Screening has reduced the incidence of the disease but the proportion of young women presenting with low-risk early-stage disease has increased. Radical hysterectomy with pelvic lymph node dissection (PLND) is the standard surgical approach for women with early stage (1A2 and 1B1) disease. The cure rate is high but women undergoing radical surgery are at risk of suffering “survivorship” issues related to long-term surgical effects, including compromised sexual, bowel and bladder function, as well as infertility. It is unclear whether less radical surgery, which has a lower morbidity is as effective. Data from the 24th annual International Federation of Gynecology and Obstetrics reported extensive variation in surgical practice; one-third underwent conization, one-third simple hysterectomy (with or without lymphadenectomy) and one-third radical hysterectomy (again with or without lymphadenectomy). The major reason for such discrepant practices is the lack of high-quality evidence upon which clinicians can base their decisions and advice to these women. There is a need to standardise treatments and to determine whether a simple hysterectomy in these women is as effective and less morbid. This can most readily be determined by a randomised trial. We have developed through the Gynaecological Cancer Intergroup a trial, led by the NCI Canada Clinical Trials Group (NCIC CTG CX.5 / GCIG SHAPE) in which women with early stage disease who would normally have a radical hysterectomy are randomised to this treatment or a more conservative simple hysterectomy. The trial uses a non-inferiority design to test whether, in the long-term, less invasive surgical approaches can maintain high rates of disease control and improve quality of life through a reduction in late-effects associated with the surgical procedure. The estimated 3 year pelvic relapse free survival (PRFS) is 96% for radical hysterectomy stage 1A1-2/1b1 patients. We would consider simple hysterectomy to be non-inferior if the 3 year PRFS was 92%. This would require 700 women world-wide to be recruited to see 49 events (pelvic relapses) at the time of the analysis. A positive trial result with demonstrably less morbidity and better survivorship would provide a good evidence base to change clinical practice.


Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Determining the role of macrophages and ageing in involution-associated mammary tumourigenesis
Funder: Medical Research Council

Abstract: Breast cancer will affect 1 in 8 women and the incidence rate is rising. While an early full-term pregnancy is protective, post-lactational involution is associated with increased risk and this risk is higher for older women. Experimental evidence in rodents demonstrated that involution is pro-tumourigenic. We hypothesise that inflammatory signalling and the macrophage phenotype during involution is tumour-promotional and that age-related changes in the involuting breast, arising in both the epithelium and the stromal cells, are responsible for the higher cancer risk in involuting older women. The purpose of the proposed project is to address four main questions to improve understanding of the effects of age and the function of macrophages in involution. Firstly, we will address whether the alternatively activated macrophage phenotype is important in promoting involution-associated tumourigenesis and determine whether Stat3 signalling in macrophages affects their phenotype and involution-associated tumourigenesis. Then we will determine if involution-associated tumourigenesis is accelerated with age and is related to macrophage function. Finally, we will derive a molecular signature of age-related changes in involuting mammary gland that will provide markers for increased risk. This project will enhance our knowledge of the critical link between inflammation and neoplastic transformation, and will suggest new approaches to prevent involution-associated tumourigenesis.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Regulating intracellular signalling pathways through integrin-mediated endocytic trafficking.
Funder: Wellcome Trust

Abstract: Integrins and signalling receptors are cell surface proteins which enable the cell to interpret its physical and chemical environment. Together these cell surface proteins dictate the fate of the cell: whether to grow, move to new surroundings, differentiate into a specialised cell or die. Integrins and signalling receptors reside at the surface of the cell, and inside the cell within specialised compartments called endosomes. Integrins are exchanged between endosomes and the cell surface, an d this movement of integrins alters the way in which signalling receptors transmit the messages that allow the cell to interpret new surroundings. I will investigate the way in which movement of integrins between endosomes and the cell surface controls signalling pathways within the cell that determine the appropriate response to the surrounding environment. Major research goals: 1. To identify the proteins that change the way in which integrins and signalling receptors move within the cell and convey their signals in moving cancer cells. 2. To use the knowledge gained from studying cancer cells to investigate how the cell s surroundings control the movement of integrins and signalling receptors within cells which are differentiating, and how this movement controls signalling pathways that lead to differentiation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The germ stem cell niche in the human testis and the origins of testicular cancer.
Funder: Wellcome Trust

Abstract: The testicles in the male contain germ cells that will provide the basis for making sperm in adulthood. In the testis germ cells communicate with surrounding supporting cells so that they can develop normally. If the germ cells fail to receive the correct signals from the supporting cells then this may result in their failure to develop normally and this will then predispose to later development of testicular germ cell cancer in adulthood. Abnormalities in certain genes or exposure to environmen tal chemicals have been proposed to affect fetal germ cell development, but this is difficult to study directly in the human fetus. This project will use transplantation of small pieces of fetal testis tissue or cells into a host animal to investigate how the cells of the fetal testicle communicate with each other in the normal situation and what sorts of factors (eg genetic conditions, chemical exposures) can make this go wrong so as to lead to abnormal germ cell development and risk of testis cancer. This will also help us to understand how disorders of sperm production and infertility can occur and identify potential means for preserving or restoring fertility in men.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Molecular mechanisms of cohesin
Funder: Medical Research Council

Abstract: Work on cohesin suggests that its triparatite rings hold DNAs together by entrapping them. The ring is made of a pair of rod-shaped Smc proteins (Smc1 and Smc3) whose association creates V shaped molecules whose vertices are connected by a third subunit called kleisin (Scc1). The long term goal of our research is to elucidate the mechanism by which cohesin rings entrap and subsequently release DNAs. This goal cannot be achieved without knowing more about the structure of cohesin's subunits and how they interact. To understand DNA entry, we need to know more about the structure of a separate Scc2/4 loading complex thought to create an entry gate by opening up the Smc1/Smc3 hinge interface, how it interacts with cohesin, how it cooperates with cohesin's Scc3 subunit during the loading process, and more about the structure of the coiled coil arms of Smc1 and Smc3. Our recent work suggests that DNA escapes from cohesin rings through creation of an exit gate at the interface between Smc3's NBD and the N-terminal domain of Scc1. We have recently solved, at least partially, the structure of this interface. Our next task is to understand how cohesin's Pds5, Scc3, and Wapl subunits cooperate to dissociate it. To do this, we need to elucidate the structure of Pds5, preferably complexed with Wapl, then to visualize, using EM how the Pds5/Wapl subcomplex along with Scc3 interacts with the Smc3/Scc1 interface. Cohesin dysfunction during meiosis in oocytes has been implicated in the genesis of aneuploidy which in addition to causing Down's syndrome (Trisomy 21) is the leading cause of age-related infertility. Defects in the loading of cohesin onto chromosomes is thought to be the cause of Cornelia de Lange syndrome, a genetic disease associated with multi-system developmental defects. Genomic instability due to replication, repair, or segregation defects plays an important part during the genesis of many tumours. Our work will therefore have important biomedical implications.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH;CONGENITAL DISORDERS
Title: Reciprocal signalling between stem cells and their microenvironment in epidermis and tumours
Funder: Medical Research Council

Abstract: Stem cell behaviour is controlled both by intrinsic mechanisms and by external signals from the local microenvironment or niche. Interactions with the niche are reciprocal, since stem cells are capable of remodelling their environment. Using adult epidermis as an experimental model, I propose to discover the relative importance of specific intrinsic and extrinsic signals in regulating stem cell fate (aim 1) and reveal how altered intrinsic signalling in stem cells impacts on neighbouring cells of the epidermis and dermis (aim 2). I will apply these findings to squamous cell carcinomas of the oral cavity (HNSCC) (aim 3). In aim 1 I will develop live cell imaging tools to visualise commitment and differentiation of single human epidermal stem cells on micro-patterned extracellular matrix (ECM)-coated substrates. I will examine whether engagement of specific intercellular receptors or attachment of stem or differentiated cells affects the decision of an adherent stem cell to differentiate. I will also investigate whether intrinsic activation of Wnt, Notch/Delta-like1 (Dll1), EGF receptor (EGFR) or beta1 integrin signalling, interconnected pathways known to affect the epidermal stem cell compartment, influences microenvironmental responses. In aim 2 I will extend the studies in vivo by examining reconstituted human epidermis in immunocompromised mice and mice in which the epidermal stem cell compartment is genetically modified. I will discover the functional significance of heterogeneous Dll1 expression by epidermal stem cells and evaluate how intrinsic epidermal alteration of Dll1, Lrig1 and beta1 integrins impacts on cells of the dermis, thereby identifying specific stromal signatures of genetic alterations in the epidermis. In aim 3 I will study the microenvironmental responsiveness of human HNSCC stem cells in vitro using tools developed in aim 1, correlating the data with HNSCC growth in xenografts. I will correlate genetic alterations with altered niche responses in vitro and with the composition of the tumour stroma in vivo, relating the data to the stromal signatures defined in aim 2. I will use this information to devise strategies to block tumour growth in xenografts. The research has broad translational applications. The micro-patterned substrates can be used to probe niche interactions in any adherent stem cell population and as a platform for drug discovery; identification of stromal signatures that reflect specific genetic alterations in epithelia will provide improved diagnostic and prognostic indicators in a wide variety of tumours; and modifying niche interactions offers an exciting strategy for treating cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;SKIN
Title: Long-term and high exposure effects of NB-UVB phototherapy in relation to increased risk of skin cancers: A 30 year retrospective cohort study in Scotland
Funder: Chief Scientist Office, Scotland

Abstract: Phototherapy (‘light treatment’) is widely used for many skin diseases. One form of light treatment called PUVA in which UVA rays are used to ‘activate’ a psoralen drug is associated with an increased risk of skin cancers. Since it was introduced (in Dundee, Scotland and Utrecht, the Netherlands) in the 1980’ s narrowband ultraviolet B (NB-UVB) has become the form of light treatment used most widely around the world to treat various skin diseases. So far, no definite increased risk of skin cancer has been detected with NB-UVB, but the studies done so far have been too small to detect anything less than a large risk. We propose a retrospective study, following on from the largest study done on this topic so far which we published in 2008. This study will involve many more patients, followed-up for longer, as it will involve all the people (about 62,753) in Scotland who have been treated with NBUVB, and we have many more years (from 1985 to 2015) of follow-up. It will allow us to better answer the question as to whether or not NB-UVB increases the risk of any of the main types (BCC, SCC, or melanoma) of skin cancers in humans.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS;SKIN