Dr Sarah McClelland

BSc, PhD
Senior Lecturer
Group Leader
Twitter
Research Focus

My lab aims to understand the mechanisms that underlie numerical and structural chromosome aberrations in cancer at a molecular level, which also involves understanding how normal cells replicate and segregate their genomes.

Key Publications

Watching cancer cells evolve through chromosomal instability. Nature News and Views (2019) 570(7760):166-167. PMID: 31182831

Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Cancer. BioRXiv (2019) doi.org/10.1101/727537

Replication stress generates multiple distinct classes of DNA copy number alteration. BioRXiv (2019) doi.org/10.1101/743658

Non-Random Mis-Segregation of Human Chromosomes. Cell Reports (2018) 23(11):3366-3380. PMID: 29898405

Replication stress links structural and numerical chromosomal instability in colorectal cancer. Nature (2013), 494:492-6. PMID: 23446422

Major Funding
  • 2018-2020- CRUK Pioneer award, £200,000
  • 2017-2020- Pancreatic Cancer Research Fund Project Grant, Identifying Mechanisms Driving Chromosomal Instability in Pancreatic Cancer,£180,000 
  • 2018-2020- Wellbeing of Women, Preventing chemotherapy resistance in Ovarian Cancer by targeting Chromosomal Instability, £130,000
Other Activities
  • Member of the British Society for Cell Biology (BSCB)
  • MDPI Cancers Young Cancer Investigator of the Year 2018
Research

My lab aims to understand the mechanisms that underlie numerical and structural chromosome aberrations in cancer at a molecular level, which also involves understanding how normal cells replicate and segregate their genomes.

Cancer cells near-ubiquitously display abnormal numbers and structures of chromosomes, termed Chromosomal Instability (CIN). CIN can promote tumour evolution and chemotherapy resistance. This means an important goal is to understand the processes generating CIN in cancer, and to develop new ways in which to target this tumour-specific feature.

To do this we run several projects in the lab to investigate how cancer cells from a panel of different cancer types (ovarian, pancreatic, prostate and colorectal) generate chromosomal instability. We also work to understand better the fundamental process of chromosome segregation during mitosis, specifically in the context of how chromosome identity can dictate behaviour during normal, and unperturbed conditions.

Cancer cells frequently exhibit abnormalities in the number and structure of their chromosomes. These abnormalities can be generated at every cell division, meaning that a population of cancer cells can contain cells that are very different to one another. This process is termed chromosomal instability, and is associated with chemotherapy resistance and poor patient prognosis.

My lab aims to understand the mechanisms that underlie numerical and structural chromosome aberrations in cancer at a molecular level, which also involves understanding how normal cells replicate and segregate their genomes. We are interested in how mechanisms generating chromosomal instability may vary between tumour types, and in using this information to understand chemotherapy resistance and create more accurate models of chromosomal instability. Ultimately we aim to improve cancer patient survival by advancing our knowledge of processes underlying tumour drug resistance, and using this to aid treatment stratification and chemotherapy design.

Current projects:

  • Mechanisms driving chromosomal instability in ovarian cancer

High-grade serous ovarian cancer (HGSOC) represents the major subtype of ovarian cancer and displays high levels of chromosomal instability. We are collaborating with the Balkwill and Lockley laboratories to investigate mechanisms driving chromosomal instability in HGSOC using cell lines, 3-D culture systems and human tissue samples.

  • Understanding the relationship between replication stress and chromosomal instability

We previously identified an important role for replication stress in promoting chromosome missegregation events in colorectal cancer. However the exact molecular mechanisms underlying the generation of chromosomal instability following replication stress are not clear. Using proof-of-principle experiments in diploid cells we aim to model these processes to better understand the link between replication stress and chromosomal instability.

  • Investigating the phenomenon of non-random chromosome mis-segregation

We recently discovered that during perturbed cell division particular chromosomes are prone to mis-segregate and become aneuploid (Worrall and Tamura et al, Cell Reports 2018). We are now investigating this phenomenon further with additional approaches to disrupt accurate genome replication and segregation.

Other Activities
  • Member of the British Society for Cell Biology (BSCB)
  • MDPI Cancers Young Cancer Investigator of the Year 2018
Major Funding
  • 2018-2020- CRUK Pioneer award, £200,000
  • 2017-2020- Pancreatic Cancer Research Fund Project Grant, Identifying Mechanisms Driving Chromosomal Instability in Pancreatic Cancer,£180,000 
  • 2018-2020- Wellbeing of Women, Preventing chemotherapy resistance in Ovarian Cancer by targeting Chromosomal Instability, £130,000
  • 2016-2018- Kay Kendall Leukaemia Fund, Modelling monosomy to understand poor prognosis in Acute Myeloid Leukaemia, £132,914
  • 2014-2017- Barts Charity, Investigating mechanisms of chromosomal instability in High-Grade Ovarian Cancer, £186,517
Recent Publications

Single-cell approaches to understand genome organisation throughout the cell cycle. McClelland SE Essays Biochem (2019) 63(2) 209-216
https://www.ncbi.nlm.nih.gov/pubmed/31092688

Impaired CENP-E Function Renders Large Chromosomes More Vulnerable to Congression Failure. Tovini L, McClelland SE Biomolecules (2019) 9(2)
https://www.ncbi.nlm.nih.gov/pubmed/30691136

The emerging links between chromosomal instability (CIN), metastasis, inflammation and tumour immunity. Tijhuis AE, Johnson SC, McClelland SE Mol Cytogenet (2019) 12(2) 17
https://www.ncbi.nlm.nih.gov/pubmed/31114634

Non-random Mis-segregation of Human Chromosomes. Worrall JT, Tamura N, Mazzagatti A et al. Cell Rep (2018) 23(2) 3366-3380
https://www.ncbi.nlm.nih.gov/pubmed/29898405

Role of chromosomal instability in cancer progression. McClelland SE Endocr Relat Cancer (2017) 24(1) T23-T31
https://www.ncbi.nlm.nih.gov/pubmed/28696210

Response to Bakhoum et al. Burrell RA, McClelland SE, Bartek J et al. Curr Biol (2014) 24(2) R150
https://www.ncbi.nlm.nih.gov/pubmed/24556434

Replication stress links structural and numerical cancer chromosomal instability. Burrell RA, McClelland SE, Endesfelder D et al. Nature (2013) 494(2) 492-496
https://www.ncbi.nlm.nih.gov/pubmed/23446422

Chromosomal instability: a composite phenotype that influences sensitivity to chemotherapy. McClelland SE, Burrell RA, Swanton C Cell Cycle (2009) 8(2) 3262-3266
https://www.ncbi.nlm.nih.gov/pubmed/19806022

For additional publications, please click here
Team

Postdoctoral Researchers in this group
Dr Alice MazzagattiDr Nadeem ShaikhDr Naoka Taylor

PhD Students
Ms Sarah Johnson, Ms Laura Tovini

Biography
  • Aug 2013: Established laboratory at the Barts Cancer Institute, Queen Mary University of London (UK).
  • Jan 2009-Aug 2013: Post-doctoral Research Fellow with Professor Charles Swanton at the Cancer Research UK London Research Institute, UK. Integrating genomics and cell biological analysis to identify genes and mechanisms promoting chromosomal instability in cancer.
  • Mar 2005-Jan 2009: Post-doctoral Research Fellow with Dr A. McAinsh at the Marie Curie Research Institute, Surrey, UK. Investigating the function of novel human kinetochore proteins.
  • Aug 2003-May 2004: Post-doctoral Research Fellow with Dr P. Bianco at the Center for Single Molecule Biophysics, State University of New York (SUNY) at Buffalo, USA. Single molecule experiments with the human recombination protein hRad54 and investigating the properties of novel DNA dyes.
  • Oct 1999-Aug 2003: PhD in Biochemistry with Dr M. Szczelkun at the University of Bristol, UK. Translocation by Type I Restriction Endonucleases