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Group

Cancer Cell Survival and Stress Response Group

Unit(s) of assessment: Allied Health Professions, Dentistry, Nursing and Pharmacy

Research theme: Health and Wellbeing

School: School of Science and Technology

Overview

Dr Coutts is a cancer cell and molecular biologist and her research group focuses on understanding how cell survival pathways link to disease progression as well as nuclear processes influencing gene expression during the stress response. Tumour growth is achieved by overriding cell cycle control and bypassing cell death mechanisms. Mechanisms influencing cell survival such as apoptosis and autophagy are key determinants of cell fate during stress. Moreover, during tumour progression the acquisition of metastatic potential is the most devastating event in human cancer with metastatic disease the cause of 90% of cancer deaths. Cancer cells adapt and respond to their microenvironment as well as therapeutic and metabolic stressors which ultimately modulate cellular outcome. Importantly, understanding how the cell integrates a variety of signals to affect cell fate is clinically and therapeutically relevant and a poorly understood process.

Our research aims to identify and understand new pathways regulating cancer cell fate during stress responses, in particular, how signalling pathways influence cell survival as well as how nuclear structure impacts on gene expression.

Current key research areas:

1. Novel pathways influencing cell survival and integration of cytoplasmic with nuclear events during the stress response.

A main aspect of the group is to explore how a p53 transcription co-factor and actin nucleation promoting factor, JMY, links the cytoskeleton with nuclear events during the stress response, how this impacts on p53 activity and cell survival, and the role of actin in these processes. In particular during the DNA damage response JMY‘s nuclear localisation promotes p53-dependent gene expression and influences DNA repair. Future work aims to identify nuclear JMY interactors and how JMY-mediated actin nucleation impacts on nuclear function.

Our research also identified a role for JMY-mediated actin-nucleation in the regulation of autophagosome formation during metabolic stress. This promotes cell survival by cytoplasmic JMY. Hanne Hansen (PGR) is undertaking a project to understand how JMY influences autophagy and how cytoplasmic JMY is regulated during metabolic stress. We are collaborating with colleagues (Dr David Boocock, Dr Clare Coveney, JvGCRC Proteomics, Dr Cristine Montiel-Duarte, JvGCRC, Gene expression group) to identify JMY interacting proteins and post-translational modifications (PTM) to better understanding how JMY is regulated during metabolic stress and how JMY’s regulation leads to autophagosome formation to impact cell survival.

We also have projects exploring other processes and pathways that influence cancer cell survival and cell cycle regulation as well as migration and disease progression. In addition, we have active collaborations with colleagues to address:

The role of microbiota-associated metabolites (MAMs) on cancer cell survival and disease progression (Prof Lesley Hoyles, NTU, AROM and Prof Udo Opperman, University of Oxford). We have a particular interest in the impact of MAMs on human cancers and the response to chemotherapeutics with a current focus on breast and pancreatic cancers.

Novel links with p53 and TAU in regulation of cell death. Together with Dr Shreyasi Chatterjee (NTU, Integrative neurophysiology) and Dr Clare Coveney and Dr David Boocock (JvGCRC, Proteomics) we are exploring a novel genetic interaction between Tau and p53 in regulating cell death as well as the Tau interactome in human cancer. We are investigating how Tau and p53 interact to influence cell death with a particular focus on breast cancer where Tau is highly expressed and is prognostic.

2. Nuclear structure and influence on gene expression.

An important aspect of our work is to understand how nuclear structure impacts on gene expression and ultimately how this influences cell survival during stress.

Dr Preeti Dinning (PDRA) is undertaking projects to explore the role of paraspeckles in cancer cell survival and how nuclear F-actin formation is regulated to impact on cell fate during stress responses. We are supported in this work by our JvGCRC Proteomics facilities (Dr David Boocock, Dr Clare Coveney) as well as external collaborators (Dr Daniel Booth, University of Nottingham).

Recent research funding

Nottingham Trent University, Health and Wellbeing PDRA fellowship. The role of paraspeckles in cancer cell survival. Aug 2023-July 2024.

British Society for Cell Biology: Summer Studentship: Regulation of p53 during autophagy. July-Aug 2020.

Nottingham Trent University, Vice Chancellor funded PhD studentship. Regulation of gene expression by JMY during the DNA damage response. Oct 2019 – Dec 2022.

Wellcome Trust Seed Award: The role of autophagy in cancer cell motility. May 2017-May 2019.

Collaboration

Dr Coutts collaborates with the following:

Dr Isabel Pires, Head of Hypoxia and Tumour microenvironment lab (University of Hull, UK)

Prof Nick La Thangue, Professor of Cancer Biology (University of Oxford, UK)

Dr Sandra Maniam, (University of Putra, Malaysia)

Prof Udo Oppermann, Professor of Molecular Biology (University of Oxford, UK)

External collaborators:

We collaborate widely with internal as well as external colleagues including: Dr Isabel Pires (University of Manchester), Dr Sandra Maniam (Universiti Putra Malaysia), Prof Nick La Thangue (Dept. Oncology, University of Oxford), Prof Ester Hammond (Dept. Oncology, University of Oxford), Prof Udo Oppermann (NDORMS, University of Oxford), Dr Daniel Booth (University of Nottingham). If you are interested in potential collaboration please get in touch.

Membership

Publications

Dr Coutts’ complete publication record can be found in her ORCiD record: https://orcid.org/0000-0002-5005-1864

Rodriguez-Pastrana, I, Biri, E, Coutts AS. p53-dependent DNA repair during the DNA damage response requires actin nucleation by JMY. Cell Death Differ, 30:1636–1647, 2023.

Functional interplay between E2F7 and ribosomal rRNA gene transcription regulates protein synthesis. Coutts AS, Munro S, La Thangue NB. (2018). Cell Death Dis, 9 (5): 577

Actin nucleation by WH2 domains at the autophagosome. Coutts AS, La Thangue NB. (2015). Nature Communication, 6: 7888

Cofactor Strap regulates oxidative phosphorylation and mitochondrial p53 activity through ATP synthase. Maniam S, Coutts AS, Stratford MR, McGouran J, Kessler B, La Thangue NB. (2015). Cell Death Differ, 22:156-163.

E2F-7 couples DNA-damage dependent transcription with the DNA repair process. Zalmas LP, Coutts AS, Helleday T, La Thangue NB. (2013). Cell Cycle, 12:3037-3051.

Hypoxia-driven cell motility reflects the interplay between JMY and HIF-1a. Coutts AS, Pires IM, Weston L, Buffa FM, Milani M, Li JL, Harris AL, Hammond EL, La Thangue NB. (2011). Oncogene 30 (48): 4835-4842.

A transcription co-factor integrates cell adhesion and motility with the p53 response. Coutts AS, Weston L, La Thangue NB. (2009). PNAS, 106 (47): 19872-19877.

Facilities

The laboratory of Dr Coutts currently houses an xCelligence RTCA DP real-time cell analyser and BD C6 Accuri flow cytometer. We also have access within the John van Geest Cancer Research Centre to instrumentation to facilitate multi-omic analyses including gene expression micro-array, Nanostring platform, mass spectrometers and laser capture microdissection.