Cancer Metabolism, Growth and Survival

Introduction

Leung head 0020

Prostate cancer is a major global health issue, and its management remains controversial. A refined understanding of how aberrant signalling drives prostate carcinogenesis will help develop better prognostic biomarkers and therapeutic targets. FGF receptor and ERK5 in particular have been implicated in prostate cancer.

Work in our lab continues to explore the significance of these signalling pathways, to investigate tumour biology using in vitro and in vivo models and to develop specific small molecule inhibitors. Working closely with colleagues in the NHS, Glasgow University and the CRUK Scotland Institute, we are developing infrastructure required for the necessary biorespository and other ongoing translational research programmes.

Potential Postdocs, Clinical Fellows and Students

We are always keen to hear from good people. Please email me (h.leung@beatson.gla.ac.uk) with a copy of your CV including the details of two referees.

 

Introduction

Inman Gareth April 2019

The transforming growth factor beta (TGFβ) superfamily comprises approximately forty related dimeric polypeptide cytokines including the bone morphogenetic proteins (BMPs), the growth and differentiation factors (GDFs), activin, nodal and the TGFβs (TGFβ1, TGFβ2 and TGFβ3). These growth factors play fundamental roles during mammalian development and act as homeostatic factors in adult life, regulating tissue repair, wound healing and the immune response. As well as having vital normal physiological functions, these factors play pivotal roles in disease pathogenesis, and the emerging importance of TGFβ and BMP signalling in cancer biology is the primary focus of our studies. Paradoxically, TGFβ can act as both a tumour suppressor and a tumour promoter. The tumour suppressor activities of TGFβ are ascribed to its ability to act as a potent negative regulator of cell proliferation and survival. As tumours progress they frequently avoid the tumour suppressive activities of TGFβ and switch their response to this cytokine and utilise it as a promoter of motility, survival, invasion, vascularisation, metastasis and immunosuppression. We have three fundamental questions that we are trying to answer in the laboratory using both in vitro cell biological and in vivo techniques coupled with analysis of primary patient tumour material:

1) How do TGFβ/BMP act as tumour suppressors and how do tumour cells avoid this?
2) How do TGFβ/BMP act on tumour cells to promote cancer progression?
3) When and where do these events occur?

Our ultimate goals are to develop therapeutics that selectively target the pro-oncogenic actions of these cytokines and to identify patient selection criteria for their deployment.

In collaboration with Owen Sansom’s laboratory, we have previously shown that both TGFBR1 and TGFBR2 are frequently mutationally inactivated in human cutaneous squamous cell carcinoma (cSCC) and that combined deletion of TGFBR1 coupled with activation of the MAPK pathway is sufficient to drive rapid invasive cSCC formation from the Lgr5+ve hair follicle bulge stem cells in the mouse. This has led us into studies profiling the molecular landscape of human cSCC. Our recent whole exome sequencing studies have identified driver genes and pathways that are implicated in cSCC progression and we are currently building upon these observations using whole genome sequencing and RNAseq in collaboration with Peter Bailey (University of Glasgow) and Irene Leigh (QMUL). There are striking similarities in the molecular landscape of all squamous cancers, and we are determining the biological roles of the genes, pathways and processes underpinning tumour progression in cSCC, head and neck SCC and the 'squamous' subtype of pancreatic cancer using in vitro, ex vivo and in vivo pre-clinical models.

 
 

 

Introduction

The aim of our group is to understand the factors regulating programmed cell death in cancer cells. Since it is known that inhibition of cell death mechanisms is a common event in tumour development, this poses problems for many forms of chemotherapy that utilise cell death pathways, leading to drug resistance.

We are investigating both known cell death regulators as well as searching for novel proteins that control cell death and chemosensitivity. We envisage that the knowledge gained from our studies will be translated and lead to the improvement of existing clinical regimens or new targets for therapeutic intervention.

 

Introduction

Huang head 069

Post-translational modifications of ubiquitin and ubiquitin-like proteins (Ubls) control myriad of cellular processes ranging from cell cycle regulation, transcription and DNA repair to virus budding. Ubls are attached to protein targets by a hierarchical cascade of enzymes involving an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase.

Defects in these pathways have been associated with diseases such as cancer, neurodegenerative disorder and viral infection. Bortezomib (Velcade) targets ubiquitin-proteasome system, is presently approved for treating multiple myeloma demonstrating the importance of the ubiquitin-proteasome pathway in anti-cancer therapies.

E3s promote transfer of Ub from E2 to the amino group of a substrate lysine, and thus play a pivotal role in determining substrate fate. In general, E3s contain an E2 binding module (HECT, RING, U-box and RING-in-between-RING) and a substrate-binding domain to facilitate Ub transfer. RING E3s are the largest class with ~600 members in the human genome. Our group applies X-ray crystallography and biochemical approaches to study the regulation, mechanistic functions and mutation-induced deregulation in RING E3s.

See more about Prof Huang's work on Cbl on the Protein Data Bank website.

Other funding:

                

 

Introduction

murphy

Oncogenic mutations do more than simply drive unscheduled proliferation – they requisition entire suites of cellular programmes that impinge upon almost every aspect of cellular function. Our overarching hypothesis is that, as tumours evolve, some of these oncogene-induced alterations will be selectively required by cancer cells to maintain viability.

We have used a synthetic lethal approach to identify kinases required by cells that overexpress c-Myc. Intriguingly, our screen identified a number of metabolic regulators, suggesting that Myc-driven tumours may be particularly sensitive to disruption of metabolic checkpoints. Indeed we have recently demonstrated that cells overexpressing Myc are critically dependent upon AMPK and the closely related kinase ARK5 in order to maintain ATP homeostasis and thereby viability (Liu, Ulbrich et al., Nature 2012). This exciting result suggests that pharmacological suppression of Ark5/AMPK may have broad therapeutic potential against a spectrum of human cancers. Furthermore, we have developed a number of conditional transgenic mouse models of cancer that enable us to humanely track the entire course of early disease through tumour initiation and progression in situ.

The use of inducible RNAi transgenic technology will now enable us to accurately model therapeutic intervention against existing tumours in mice with a higher degree of genetic "on-target" certainty than is typically afforded by nascent pharmacological agents. The use of these models to complement cell culture based approaches is essential for a complete mechanistic understanding of the many processes involved in cancer as well as for more realistic pre-clinical evaluation of candidate therapies.

University of Glasgow- Colour

University of Glasgow webpage

Other funding:

     British Lung Foundation logo                                           

 

Introduction

Tait 2023

Cell death is a key tumour suppressor mechanism that must be inhibited in order for cancer to develop. Sensitivity to cell death also governs therapeutic efficacy because anti-cancer therapies often act by killing cells. The major form of programmed cell death is apoptosis, a process in which mitochondria play an essential role. Our research focuses upon understanding how mitochondria control cell death and addressing how this is deregulated in cancer. Clinical translation of our findings should lead to improvements of existing therapies and development of new approaches to enable tumour selective killing.

University of Glasgow webpage

Other funding:   

              Prostate Cancer UK logo

 

Introduction

Miller head 071

The Computational Biology group is focused on using data-driven approaches from machine learning to develop a better understanding of the processes that underpin tumour growth and development. We are a highly interdisciplinary group that integrates computer science, mathematics, bench- and clinical science.

A major aspect of our work is the use of cancer ‘omics data generated by large-scale tumour sequencing projects. These datasets are large enough to use machine learning algorithms that seek to correlate patterns with phenotype. This is allowing us to explore aspects of tumour evolution, and to ask how the regulatory systems that control gene expression are perturbed in tumour cells.

Our group is particularly interested in the regulatory pathways that act downstream of transcription, including the processes that govern how alternative splicing is coordinated across different pathways. Other projects in the group focus on uncovering novel regulatory sequences within the genome, and in making use of comparative genomics to help interpret the genome rearrangements that occur in tumour cells.

Other funding:

 

Introduction

Roberts 2023

Tumour immunotherapy, most notably checkpoint blockade therapy, has produced remarkable benefits for patients with cancers that previously had poor outcomes. Blockade of the T cell inhibitory checkpoint molecules CTLA-4 and PD-1 has led to dramatic remissions that have lasted more than a decade in many patients. However, these responses are unfortunately restricted to only a subset of patients. Our work broadly aims to understand how the immune response to cancer is generated so as to understand what may limit the quality or quantity of that response. In this way, we hope to find new means of augmenting the response to immunotherapy in a broader subset of patients.

To do this, we are focusing on how the T-cell-mediated immune response is initiated. T cell responses begin in the lymph node, where they are directed by signals received from the peripheral tissue, where the challenge occurs. During responses to viruses, numerous signals drive re-organisation of the lymph node and choreograph a highly regulated process by which appropriate T cell activation can occur. It has been observed that the tumour-draining lymph node is improperly activated, suggesting priming may be less efficient against the tumour. Indeed vaccination, which improves priming, can improve immunotherapeutic approaches in mice, suggesting this as a viable approach. As such, our aim is to determine how the periphery communicates with and educates the lymph node during an efficient immune response and how this is subverted in the tumour setting. Of particular interest to us is the role of different dendritic cell subsets in organising and directing efficient immune responses in the lymph node, and how these are manipulated by the tumour microenvironment. In this way, we aim to discover signals by which we can convert the lymph node microenvironment into a more effective site of immune priming to augment existing immunotherapeutic responses.

 

Introduction

Prostate cancer is a leading cause of cancer mortality in men in the western world. Identifying and understanding the pathways that drive advanced and treatment-resistant prostate cancer will provide important information that will allow prognostication and individualised patient treatments.

Androgens have been found to be important for prostate cancer progression and androgen deprivation therapy is usually effective at initially controlling the disease. In many cases, however, there is a recurrent castration-resistant phase, for which there is no effective treatment.

Our current research interest is in understanding the mechanisms of treatment-resistance in advanced prostate cancer. Work in my laboratory uses state-of-the-art in vivo models in conjunction with patient samples to interrogate the disease processes in advanced and treatment-resistant prostate cancer. This work will help to provide information on drivers of prostate cancer progression and to identify novel biomarkers of disease and/or drug targets to treat the disease.

Starter Grant for Clinical Lecturers awardee

Prof Imran Ahmad explains how a Starter Grant from the Academy of Medical Sciences allowed him to continue his research following his PhD. Click here to read the interview.

Introduction

Lewis David 0054

Cancer cells are metabolically reprogrammed to provide the energy and biomass required to proliferate. The resulting metabolic phenotype is driven by genetic mutations and a nutrient-deprived microenvironment. Differing mutations and substrate availability create a dynamic and metabolically heterogeneous tumour. This heterogeneity drives tumour recurrence, metastasis and drug resistance leading to a poor clinical outcome for cancer patients.

Molecular imaging can non-invasively measure the spatial and temporal dynamics of cancer metabolism. Research in our group uses state-of-the art PET/MR imaging, metabolomics and genomics to understand the drivers and consequences of metabolic heterogeneity in living tumours. The goal of this research is to develop methods to non-invasively classify tumours and to direct cancer treatment.

Radionuclide imaging of lung tumour development (place cursor over image to play video):

d lewis image

Young Investigator of the Year Award Finalist (World Molecular Imaging Congress, New York), 2016

See the following interviews about Dr Lewis' work:

Other funding:

              

       CRUK Glasgow Centre

 

Introduction

Bushell head 115

The dysregulation of protein synthesis in the tumour clone and the supporting stroma is essential for the delivery of oncogenic gene programmes that allow the establishment of both the intracellular and extracellular environments. This is driven by two fundamental post-transcriptional processes. First, hyperactivation of the eIF4F translation initiation complex results in the specific upregulation of oncogenic mRNAs. Secondly, a fundamental shift within tRNA pools promotes oncogenic gene expression programmes by altering the protein synthesis landscape. Recent data from our group and others show that these two processes are coordinated by a number of distinct regulatory RNA-binding complexes and suggest that there is cross-talk between these key steps of the translation process. Our current hypothesis is that these complexes control and connect all post-transcriptional stages of the mRNA lifecycle, from selection, through decoding, to turnover.

The balance of expressed tRNA and codon usage of oncogenic mRNAs that are sensed by these complexes represent a targetable axis of the malignant phenotype, which could be explored therapeutically if mechanistic understanding was available.

The research in our laboratory focuses on understanding how RNA-binding protein complexes, tRNA abundance and codon optimality dictate oncogenic protein production in a coordinated manner. We employ biochemical, biophysical and computational methods to address these questions. We are interested in how the changing tumour environment results in the redeployment of mRNA-binding complexes that control the balance between upregulation of protein translation and mRNA turnover and translational silencing. These mechanistic insights drive our endeavours in designing assays and drug discovery pipelines to target the heart of tumour cell biology.

Other funding:
 
 
   

 

Introduction

Gammage head 2020 067

Mitochondria are a cellular nexus, performing numerous signalling, biosynthetic and bioenergetic functions. In humans, mitochondria are composed of ~1200 proteins, the vast majority encoded in nuclear DNA, with a minor subset encoded in the spatially and heritably separate mitochondrial DNA (mtDNA).

The human mitochondrial genome is a genetically compact, circular, double-stranded DNA molecule of 16.5 kb, typically present at between 100 and 10,000 copies per cell on a cell type-specific basis. Encoded exclusively in mtDNA are subunits of the mitochondrial respiratory chain and ATP synthase, required for functional oxidative phosphorylation, and all RNA components necessary for their translation by mitochondrial ribosomes.

Mutations, deletions and rearrangements of mtDNA are a known source of hereditary metabolic disease in humans, causing a broad spectrum of pathology underpinned by mitochondrial dysfunction. Mutations of mtDNA are also found in approximately 60% of all solid tumours, often at levels that would result in profound mitochondrial dysfunction.

Mitochondrial dysregulation and dysfunction, particularly a switch from oxidative to glycolytic metabolism, is often observed in cancer. Our research focuses on determining the role of mitochondrial genetics and gene expression in human cancer.

Payam Figure

 Other funding:

LOGO ERC 2020NIH logo squareCRH logo squareScreenshot 2023 12 14 150234

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