Prof Payam Gammage - Mitochondrial Oncogenetics

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

Prof Martin Bushell - RNA and Translational Control in Cancer

Introduction

Bushell

The Bushell laboratory's work focuses on the interplay between two key mRNA regulatory hubs, the eIF4F and CCR4-NOT complexes, which control the fate and expression of mRNA and are fundamentally dysregulated and a hallmark of cancer. These complexes act as master switches, ensuring that the necessary proteins are made to support cell growth and survival. However, when dysregulated, these factors can drive malignant programmes. We are examining how these complexes are dysregulated and how this dysregulation mechanistically results in the production of oncogenic gene expression programmes. We use an array of approaches, spanning from reconstitution of purified recombinant components with enzymology to advanced bespoke next-generation sequencing methods, coupled with bioinformatics analysis and machine learning approaches, to cover control mechanisms and information embedded within the oncogenic expression landscapes.

eIF4F complex: Driving Translation and Oncogenic Programmes

The eIF4F complex is the central regulator of translation initiation, functioning at the 5' end of the mRNA. It is composed of the cap-binding protein eIF4E, the scaffold protein eIF4G, and the RNA helicase eIF4A1. Its primary role is to unwind secondary structures in the mRNA's 5'-untranslated region (UTR), enabling the ribosome to associate and begin ribosomal scanning to find the translation start codon. Dysregulated eIF4F activity is a known driver of malignant transformation, since it lies at the nexus of multiple oncogenic signalling cascades. Oncogenes like c-Myc are especially dependent on eIF4F because their 5'-UTR often has highly structured RNA elements that under healthy conditions act to repress translation, limiting their oncogenic potential. We are dissecting how the eIF4F complex is driving these oncogenic gene expression programmes, focusing on understanding why oncogenic mRNAs are specifically commanded by this complex in the oncogenic setting. Additionally, we are exploring how different subunits and associated components are involved in delivering the different oncogenic activities of this complex.

CCR4-NOT complex: Sensing the mRNA Code and Directing Fate

The CCR4-NOT complex controls mRNA turnover and stability and is recruited by miRNAs and an array of RNA binding proteins that act to initiate mRNA decay through its associated deadenylases. It is a large complex with many associated factors, several of which are known to function in both translational repression and mRNA decay. It has been known for many years that its function in mRNA decay is critically intertwined with protein synthesis, but how has remained elusive. We and others have recently found that this complex senses the speed of ribosome decoding through the CNOT3 subunit, which physically interacts with the ribosome only when it is moving slowly across the mRNA. Ribosome decoding speed is intimately connected to the availability of amino acid charged tRNA. Thus, through the CCR4-NOT complex, decoding speed dictated by available tRNAs is coupled to mRNA decay. However, our data suggest that this level of regulation is much more complicated and is critical to allow correct and functional proteome establishment at many levels. We are investigating the role of this CCR4-NOT complex in cancer, where we know tRNA deployment can alter and change the amount of protein and the decoding rate at which it is made. How does it control and sculpt the oncogenic gene expression landscape? How do changes in protein production change protein functionality?

The Therapeutic Opportunity

These opposing and distinct functions of eIF4F and CCR4-NOT in controlling gene expression programmes open opportunities for therapeutic targeting. We are working to understand the molecular details that determine which mRNAs are controlled by which complex, enabling the rational design of compounds that can selectively interfere with the aberrant oncogenic programmes driven by these two powerful master regulators at different stages of cancer development.

Other funding:
 
 
   

 

Prof Imran Ahmad - Models of Advanced Prostate Cancer

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.

Prof David Lewis - Molecular Imaging

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:

           RadNet Glasgow   

       CRUK Glasgow Centre

 

Prof Crispin Miller - Computational Biology

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:

 

  1. Dr Ed Roberts - Immune Priming and the Tumour Microenvironment
  2. Prof Stephen Tait - Mitochondria and Cell Death
  3. Prof Daniel J Murphy - Oncogene-Induced Vulnerabilities
  4. Prof Danny Huang - Ubiquitin Signalling

Opportunities

Read More

Events

Read More

Recent Publications

Read More

What's Happening Now

Focal adhesion Jamie Whitelaw

See our most recent publications

Melanoma cells 2

Click here to see current job vacancies at the Scotland Institute

Latest News

Latest cancer news stories

Feed not found.

Cancer Research UK Scotland Institute

The Beatson Institute for Cancer Research, a Registered Scottish Charity No SC006106 & Company Limited by Guarantee (Registered in Scotland No 84170) [trading as the Cancer Research UK Scotland Institute]

Get in Touch

call +44(0) 141 330 3953

reception@crukscotlandinstitute.ac.uk

Garscube Estate Switchback Road Bearsden Glasgow, G61 1BD

See our Wikipedia page