Garnett Group
Translational Cancer Genomics
Research foci
There are currently four complementary research focuses in my laboratory:
- The genomics of drug sensitivity. High-throughput drug screens in human cancer cell cultures to identify genetic features of cancer cells that are predictive of drug sensitivity.
- Mapping synthetic-lethal dependencies in cancer cells. Genome-wide CRISPR-Cas9 synthetic-lethal screens in cancer cell lines to identify potential new oncology drug targets.
- A new generation of organoid cancer models. Methods for the derivation, characterisation and use of a new set of cancer organoid in vitro cell culture models.
- Tumour-immune cell interactions. The use of patient-derived in vitro co-cultures to understand mediators of tumour and immune cell interactions.
These studies are intergrated into our Cancer Dependency Map initiative, which aims to identify all dependencies in cancer cells to help guide future precision cancer medicines.
Background
Cancer is a genetic disease caused by the accumulation of changes within the DNA of cells that confers a growth and survival advantage. Cancer is not just one disease, but many different diseases, each with a different spectrum of underlying genetic causes. The functional consequence of these genetic changes in the genes of healthy and cancer cells is often poorly understood, and how they contribute to disease is often unclear. Furthermore, these genetic changes can impact on patient responses to therapy and consequently can be used to select patients most likely to benefit from a specific treatment.
The Translational Cancer Genomics team investigates how genetic alterations in cancer contribute to disease and impact on response to therapy. Our research is at the interface of cancer genomics, cell biology and cancer therapeutics and employs high-throughput biology approaches together with detailed mechanistic studies.
The team have state-of-the-art facilities to perform their research including extensive robotics, acoustic dispensing, high-content microscopy, CRISPR and chemical libraries, and access to core Sanger IT and genomics infrastructure.
Seminars and talks from the team, as well as tutorials for our public databases, are available to view on Twitter.
The genomics of drug sensitivity
The team uses high-throughput drug sensitivity screens in highly annotated human cancer cell cultures to identify genetic features of cancer cells that are predictive of drug response.
The collection of cancer cell models to study drug response includes >1000 human cancer cell lines, organoids, and engineered mouse and human cells. Cell culture models are highly annotated at the level of the genome (DNA sequencing), transcriptome (gene expression and RNAseq), epigenome (DNA methylation), and proteome. The team perform single-drug and combination screens with hundreds of anti-cancer compounds across their large collection of cell culture models to detect drug sensitivity in specific tissue and genetic sub-types.
The results from these screens are used to improve the design of clinical trials through the identification of patient populations most likely to respond to a therapy.
This research is performed in partnership with the laboratory’s of Ultan McDermott and Mike Stratton within the Cancer Genome Project at the Sanger Institute. The results of this work are available from the Genomics of Drug Sensitivity in Cancer database.
Mapping synthetic-lethal dependencies in cancer cells
Mathew’s group are performing genome-wide CRISPR-Cas9 synthetic-lethal screens in cancer cells to identify potential new oncology drug targets in defined genetic backgrounds.
The complexity and diversity of cancer genomes represents a significant challenge when developing new cancer therapies. Specifically, identifying cellular signalling nodes and processes whose perturbation selectively kills cancer cells while sparing normal cells remains acutely difficult. This is because our understanding of which proteins are necessary for cancer cell survival is incomplete. Furthermore, our understanding of cellular networks and processes is relatively poor in normal cells, let alone in the context of cancer cells with their myriad of molecular alterations. Thus, systematic and unbiased approaches to identify critical dependencies in cancer cells could significantly expand the repertoire of new drug targets for future development.
Genome-editing technologies such as CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats) are a powerful tool for studying gene function in normal and diseased cells. This approach uses a single guide RNA (sgRNA) to recruit the Cas9 endonuclease to a desired genomic loci to create double strand breaks, which are repaired through an error prone process resulting in targeted gene inactivation. Taking advantage of the programmable nature of the sgRNA, it is now possible to use a library of sgRNAs to perform genome-wide functional genetic screens across a diverse array of cellular models and systems.
Mathew’s group, in collaboration with the laboratory of Kosuke Yusa, are exploiting CRISPR-Cas9 genome-editing technology to systematically identify new drug targets using genome-wide ‘synthetic lethal’ screens in cancer cell lines. The identification of acute sensitivities, which occurs within specific molecular/genetic sub-types, could provide novel opportunities for genetically targeted therapeutic intervention. The results of our CRISPR screens and target prioritisation are available through the Project Score database.
A new generation of organoid cancer models
Approximately 1,000 human cancer cell lines are available to scientists worldwide and this has been a useful resource for cancer research. However as we enter the era of precision medicine, poor representation of some cancer types, insufficient numbers to capture the genetic diversity of cancer, lack of clinical outcome data and lack of comparison to normal reference sample limit their use.
Novel cell culturing methods such as organoid derivation have revolutionised our ability to derive cell line models from both healthy and diseased tissue, and have the potential to overcome these limitations.
We are generating and characterising new patient-derived cancer cell line models from different tumour types as experimental tools. These cell lines are being characterised at the level of the genome and transcriptome, profiled for differential sensitivity to anti-cancer therapies, and are being made available to the research community. These models are being generated as part of an international collaboration called the Human Cancer Model Initiative, led by the Sanger Institute, the U.S. National Cancer Institute, and Hubrecht Organoid Foundation.
Organoid models generated by Sanger are for sale through American Type Culture Collection.
Our Cell Model Passports database hosts cell model genetic and functional datasets.
We anticipate that this highly annotated resource will have broad applications and serve to catalyse a new wave of discovery in fundamental cancer biology and therapeutics.
Tumour-immune cell interactions
Immunotherapies against PD1 and CTLA-4 are effective for the treatment of multiple tumour types and lead to durable responses for some patients. However, these therapies – referred to as checkpoint blockade – are not effective for all cancer types and the duration of responses remains poorly understood. The pre-clinical development of new immunotherapies is difficult because of a lack of human models systems that effectively mimic the interaction of the tumour and immune system.
We are developing new in vitro co-cultures models of patient-derived organoids together with immune cells to study the cellular factors that mediate immune cell mediated tumour cell killing.
The development of these models, and their use for the study of tumour-immune cell interactions, could lead to a deeper understanding of factors influencing patients responses to checkpoint blockade and new therapuetic hypotheses.
Core team
Mrs Angham Al Saedi
Advanced Research Assistant
Syd Barthorpe
Senior Scientific Manager
Grace Battarbee
Research Assistant
Alexandra Beck
Project Manager
Theo Bell
Research Assistant
Mr Shriram G Bhosle
Principal Software Developer
Cansu Dincer
PhD Student
Dr Olli Dufva
Postdoctoral Fellow
Kim Evans
Research Assistant
Maria Garcia-Casado
Research Assistant
Dr Frederik Gibson
Cellular screening specialist
Dr Carmen Herranz-Ors
Postdoctoral Fellow
Dr Liliya Kopanitsa
Advanced Research Assistant
Dr Howard Lightfoot
Principal Bioinformatician
Dr Katrina McCarten
Postdoctoral Fellow
Dr Clare Pacini
Principal Bioinformatician
Dr Saroor Patel
Senior Staff Scientist
Gabriele Picco
Postdoctoral Fellow
Mamta Sharma
Senior Technical Specialist
Rebecca Shepherd
Senior Bioinformatician
Tzen Szen Toh
Wellcome Trust Clinical PhD Fellow
Samantha Walker
Research Assistant
Previous core team members
Rizwan Ansari
Advanced Research Assistant
Dr Fiona Behan
Postdoctoral Fellow
Graham Bignell
Senior Staff Scientist
Sophie Brocklesby
Research Assistant
Jessica Cantwell
Research Assistant
Elisabeth D. Chen
PhD Student
Dr Matthew Coelho
Cancer Research UK Career Development Fellow
Dr Thomas Cokelaer
Senior Bioinformatician
Dr Lisa Dwane
Postdoctoral Fellow
Luke Farrow
Research Assistant
Hayley Francies
Senior Staff Scientist
Mr James Gilbert
Senior Software Developer
Emma Goffin
Former Advanced Research Assistant at the Sanger Institute
Emanuel Gonçalves
Postdoctoral Researcher
Caitlin Hall
Research Assistant
Dr Patricia Jaaks
Staff Scientist
Maciej Jablonski
Research Assistant
Megan Jukes
Research Assistant
Genevieve Leyden
Research Assistant
Ermira Lleshi
Research Assistant
Mr Iman Mali
Research Assistant
Emily Mallett
Research Assistant
Mr Kieron May
Research Assistant
Ms Anne Maria McLaren-Douglas
Senior Research Assistant
Tatiana Mironenko
Senior Research Assistant
James Morris
Research Assistant
Dr Romina Oliveira Silva
Staff Scientist
Riccardo Panero
Postdoctoral Fellow
Rachel Pooley
Research Assistant
Stacey Price-Weight
Head of Technical Development - DNAP
Mrs Laura Richardson
Advanced Research Assistant
Mr Gabriel Robert-Tissot
Research Assistant
Dr Marie Shamseddin
Postdoctoral Fellow
Mr Massimiliano Jacob Spensley
Research Assistant
Ms Fran Thomas
Research Assistant
Charlotte Tolley
Advanced Research Assistant
Dr Sara Valentini
Genomic Surveillance Business Analyst and Continuous Improvement Lead
Sara Vieira
Advanced Research Assistant
Mr Alex Watterson
Advanced Research Assistant
Wendy Yang
Senior Software Developer
Associated research
Related groups
Programmes and Facilities
Partners
We work with the following groups
External
Wellcome Trust
External
Open Targets
External
Cancer Research UK
External
Stand Up To Cancer
External