Modelling of tissue level carcinogenesis through hybrid, biophysical, and executable approaches

Lead Research Organisation: University of Cambridge

Abstract

Cancer is a major health concern, with one in three adults developing the disease over their lifetime. However, on a cellular level, the probability of a cell developing into a tumour is very low. Cells prevent the development of tumours through a combination of mechanisms, which operate over different scales. Within a single cell, proteins and genes form signalling pathways which reliably interpret and respond to both the cell state and the cell environment, including specific signals passed from other cells. At the same time, within a tissue, the movements and locations of cells can add a further layer of control, by limiting the communication between cells and mixing populations of cells. I will build mathematical representations (a “model”) of the early stages of tumour formation in cancer which bridges these two phenomena. By running simulations using this model, I will learn more about how the signalling and physical components combine to control cell growth and death in the oesophageal epithelium. I will further mutate and wound my model, to explore how these events can cause a breakdown of the controlling mechanisms and lead to tumour growth.

Technical Summary

Cancer is an important and widespread disease, with roughly one in three adults developing the illness in their lifetime. However, the likelihood of a single cell from the hundreds of trillion cells in the adult human body at any one time developing into a tumour is very low due to intrinsic mechanisms of suppression. Stem cells in the body are made robust to deleterious mutations by a large number of poorly characterised mechanisms. One such mechanism for limiting the damage done by mutations is the competition of stem cells within a population. Whilst recent experimental evidence has given us insight into this competition, observing the dynamics of tissue development experimentally is arduous, and requires use of animals.
The objective of this program is to develop models which give insights into experimentally inaccessible phenomena in the development of cancers, by coupling developmental and physical effects within cells. Some of these models will couple the physical dynamics of cells in the tissue with models of the underlying signalling networks to give us insights into the competition between different mutations. I will use these models to explore the nature of tissue growth and study how external events, such as wounding, can alter this competition and trigger stable populations of cells to develop into a tumour. By explicitly modelling the 3D structure of the tissue, the models will allow us to gain insights into the early stages of tumour formation by showing how changes in stratification rate and shape of the basal layer of stem cells are correlated to changes in cell proliferation rate. Alongside this, I will model cellular localisation processes, working on the dynamics and behaviours of mitochondria in the control of metabolic pathways in cancer cells.
These insights will both suggest new experiments, and highlight the most fruitful lines of experimental enquiry. As such, this programme of work will involve extensive collaboration with different members of the cancer unit. By coupling the expertise of the group, with my own skillset, I will develop a set of approaches and discoveries which guide and support our understanding of cancer development.

Publications

10 25 50
 
Description Azure for Research
Amount $20,000 (USD)
Organisation Microsoft Research 
Sector Private
Country Global
Start 11/2016 
End 11/2017
 
Description MRC Capital Bid
Amount £42,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 04/2018
 
Description MRC NIRG
Amount £423,706 (GBP)
Funding ID MR/S000216/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2018 
End 12/2021
 
Description Microsoft PhD Scholarship
Amount £71,650 (GBP)
Funding ID Paper#30 
Organisation Microsoft Research 
Sector Private
Country Global
Start 10/2016 
End 09/2019
 
Description Royal Society (Paul Inst) - The cell as a cell phone
Amount £447,097 (GBP)
Funding ID UF130039 
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 10/2014 
End 09/2019
 
Description Royal Society - Hybrid Models of Early Carcinogenesis
Amount £124,477 (GBP)
Funding ID RG14040440 
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 11/2015 
End 10/2018
 
Description Royal Society Enhancement
Amount £82,900 (GBP)
Funding ID RGF\EA\180224 
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 01/2018 
End 01/2022
 
Description Bacterial osmoregulatory signalling 
Organisation University of Portsmouth
Department School of Pharmacy and Biomedical Sciences Portsmouth
Country United Kingdom 
Sector Academic/University 
PI Contribution Training and hosting of students from Dr Draheim's laboratory in the use of Gromacs and the Sidekick simulation software. Discussion and writing of the manuscript, and analysis of the simulation outputs.
Collaborator Contribution Experimental methods and validation.
Impact Publication currently under review, available as a pre-print https://www.biorxiv.org/content/early/2018/02/03/206888
Start Year 2015
 
Description Bacterial vancomycin resistance and signalling 
Organisation Oxford Brookes University
Country United Kingdom 
Sector Academic/University 
PI Contribution I have developed computational models of the transmembrane domain of different vancomycin receptors, synthetic peptides and bacterial signalling proteins from different bacterial species. These have been used to aid synthetic protein design and test bacterial membrane models.
Collaborator Contribution The partners have developed synthetic reporter systems that allow the antibiotic responses of receptor domains (derived from the vancomycin receptor) from different bacterial species to be measured.
Impact Peer reviewed abstract: Carbon Nanoparticles and Their Differential Association with the Membranes of E. coli: A Coarse-Grained Molecular Dynamics Simulation Study
Start Year 2010
 
Description Bacterial vancomycin resistance and signalling 
Organisation University of Portsmouth
Country United Kingdom 
Sector Academic/University 
PI Contribution I have developed computational models of the transmembrane domain of different vancomycin receptors, synthetic peptides and bacterial signalling proteins from different bacterial species. These have been used to aid synthetic protein design and test bacterial membrane models.
Collaborator Contribution The partners have developed synthetic reporter systems that allow the antibiotic responses of receptor domains (derived from the vancomycin receptor) from different bacterial species to be measured.
Impact Peer reviewed abstract: Carbon Nanoparticles and Their Differential Association with the Membranes of E. coli: A Coarse-Grained Molecular Dynamics Simulation Study
Start Year 2010
 
Description Bacterial vancomycin resistance and signalling 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution I have developed computational models of the transmembrane domain of different vancomycin receptors, synthetic peptides and bacterial signalling proteins from different bacterial species. These have been used to aid synthetic protein design and test bacterial membrane models.
Collaborator Contribution The partners have developed synthetic reporter systems that allow the antibiotic responses of receptor domains (derived from the vancomycin receptor) from different bacterial species to be measured.
Impact Peer reviewed abstract: Carbon Nanoparticles and Their Differential Association with the Membranes of E. coli: A Coarse-Grained Molecular Dynamics Simulation Study
Start Year 2010
 
Description Executable modelling of cancer metabolic networks 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Developing network models and analysing large datasets of metabolic changes in cancer
Collaborator Contribution Shared datasets, expertise, and training of members of my lab.
Impact This is a multidisciplinary project, involving mathematical modelling, data science, and experimental techniques in cancer metabolism
Start Year 2018
 
Description Executable modelling of cancer metabolic networks 
Organisation University of Cambridge
Department MRC Cancer Unit
Country United Kingdom 
Sector Public 
PI Contribution Developing network models and analysing large datasets of metabolic changes in cancer
Collaborator Contribution Shared datasets, expertise, and training of members of my lab.
Impact This is a multidisciplinary project, involving mathematical modelling, data science, and experimental techniques in cancer metabolism
Start Year 2018
 
Description Formal verification of biological models 
Organisation Microsoft Research
Department Microsoft Research Cambridge
Country United Kingdom 
Sector Private 
PI Contribution Provide biological expertise that is used to help drive tool development forward
Collaborator Contribution MSR develops and supports new tools for analysing and simulating biological models, supported by computer scientists at Leicester.
Impact This is an interdisciplinary collaboration (computer science and computational biology). Two papers have arisen from the work. Emergent Behaviours of Stem Cells in Organogenesis Demonstrated by Hybrid Modelling Drug Target Optimization in Chronic Myeloid Leukemia Using Innovative Computational Platform
Start Year 2014
 
Description Formal verification of biological models 
Organisation University of Leicester
Department Department of Computer Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide biological expertise that is used to help drive tool development forward
Collaborator Contribution MSR develops and supports new tools for analysing and simulating biological models, supported by computer scientists at Leicester.
Impact This is an interdisciplinary collaboration (computer science and computational biology). Two papers have arisen from the work. Emergent Behaviours of Stem Cells in Organogenesis Demonstrated by Hybrid Modelling Drug Target Optimization in Chronic Myeloid Leukemia Using Innovative Computational Platform
Start Year 2014
 
Description Modelling clonal competition in epithelial tissues (Prof P Jones) 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Phil Jones' laboratory studies the growth of individual clones in epithelial tissues, generating a broad array of datatypes. My research team develop models of clonal development and competition that allow for the quantification of key parameters. The mathematical models further aid hypothesis development, allowing us to explore how the tissue grows and develops in response to mutation.
Collaborator Contribution Phil Jones' laboratory studies the growth of individual clones in epithelial tissues, generating a broad array of datatypes. My research team develop models of clonal development and competition that allow for the quantification of key parameters. The mathematical models further aid hypothesis development, allowing us to explore how the tissue grows and develops in response to mutation.
Impact Manuscripts presently under review
Start Year 2015
 
Description Modelling the structure of IKK Gamma 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I developed a computational model of the structure of a protein from experimental data, and developing simulation based techniques to validate the model.
Collaborator Contribution My partners performed biological experiments to determine the behaviour of the protein and physical experiments to give insights into the molecular structure using advanced labeling technologies (EPR).
Impact The collaboration is multi-disciplinary (molecular biology, computational biology, biophysics). The full structure of IKK-Gamma lead to the publication of the paper: Probing the solution structure of i?b kinase (ikk) subunit ? and its interaction with kaposi sarcoma-associated herpes virus flice-interacting protein and ikk subunit ß by epr spectroscopy JBC 2015
Start Year 2012
 
Description Modelling the structure of IKK Gamma 
Organisation University College London
Department MRC Centre for Medical Molecular Virology
Country United Kingdom 
Sector Public 
PI Contribution I developed a computational model of the structure of a protein from experimental data, and developing simulation based techniques to validate the model.
Collaborator Contribution My partners performed biological experiments to determine the behaviour of the protein and physical experiments to give insights into the molecular structure using advanced labeling technologies (EPR).
Impact The collaboration is multi-disciplinary (molecular biology, computational biology, biophysics). The full structure of IKK-Gamma lead to the publication of the paper: Probing the solution structure of i?b kinase (ikk) subunit ? and its interaction with kaposi sarcoma-associated herpes virus flice-interacting protein and ikk subunit ß by epr spectroscopy JBC 2015
Start Year 2012
 
Title BioModelAnalyzer 
Description BioModelAnalyzer is a platform for the development and analysis of biological network models. It primarily uses formal verification approaches, developed in software research, to analyse complex models. 
Type Of Technology Software 
Year Produced 2017 
Open Source License? Yes  
Impact Software has been adopted by AstraZeneca and is being used to model new biological networks rapidly and where precise quantities are not available. 
URL https://github.com/Microsoft/BioModelAnalyzer
 
Title BioModelAnalyzer 
Description Working with AstraZeneca and Microsoft Research, my team developed a library of reusable motifs to make model construction easier. These motifs have been written up as a manuscript (under review, and available as a pre-print https://www.biorxiv.org/content/early/2018/01/18/249888). We have further developed a novel interface to access these motifs available from the github repository. A test deployment (intended to go into production 5/3/2018) is available http://bmainterfacetest.azurewebsites.net/ 
Type Of Technology Software 
Year Produced 2018 
Open Source License? Yes  
Impact This has supported the take up of the tool by AstraZeneca by demonstrating the expressivity of the underlying mathematical formalism, and has lead to its adoption by researchers within AZ. 
URL http://biomodelanalyzer.org/
 
Title ProPPA 
Description ProPPA is a software developed at the University of Edinburgh by the group of Professor Jane Hillston. The tool allows inference of parameters in continuous models through a variety of different algorithms. 
Type Of Technology Software 
Year Produced 2017 
Impact My group has contributed bug reports, feature requests and code to the ProPPA tool, supporting development and adoption of the tool in the life sciences. 
URL https://github.com/ageorgou/ProPPA
 
Title Sidekick (automated transmembrane helix simulation) 
Description Sidekick automates the high throughput molecular dynamics simulation of transmembrane helices, from an input sequence. Systems are constructed, simulated, and analysed in an wholly automated process that can be controlled through a web based GUI. 
Type Of Technology Software 
Year Produced 2015 
Open Source License? Yes  
Impact This software is used by different groups in the UK who have joined my lab to learn how to deploy and develop the tool. 
URL https://github.com/hallba/Sidekick
 
Description A-level student projects 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact A 4-week project in structural biology of ion channels was developed for an A-level student (Upasana Das). The student learned how to use unix, build homology models, visualise protein structure and compare and contrast epilepsy causing mutations with cancer associated mutations. The student was awarded a CREST Gold award for a report written about the work done in my laboratory. Additionally, my laboratory hosted another A-level student for a week who worked on analyzing BioModelAnalyzer models of cancer.
Year(s) Of Engagement Activity 2017
 
Description Big Biology Day 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The Biog Biology Day is an annual event organised at the Hills Road Sixth Form College in Cambridge. Attended by well over 1000 people overall, the event draws expertise from both the local scientific and biotech/pharma community and helps reach out to children across a wide age range and to accompanying adults alike, from across the region. Dr David Shorthouse from the Ben Hall laboratory of the MRC CU demonstrated the use of Modelling and Computational approaches in the study of diseases such as Cancer and drew a lot of attention to this approach, including from reprresentatives of school examination boards.
Year(s) Of Engagement Activity 2015,2016
URL http://www.hillsroad.ac.uk/college-life/events/2016/10/15/default-calendar/big-biology-day
 
Description Filming of the work and motivations of the Hall group 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Two videos were generated describing work in my laboratory. One showed me explaining the motivations for my work and the broad overview of the lab, whilst the second showcased individual work in the laboratory. The videos raised awareness of the work done in my laboratory (full video views totally ~250, associated tweet engagements >3500) and led directly to new discussions with researchers in other institutions (Moffit Cancer Centre, University of Oxford). It further directly led to one student application to join the group.
Year(s) Of Engagement Activity 2017
 
Description MRC Festival of Science 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Software demonstrations, activities, and talks given by myself and my laboratory to A-level students
Year(s) Of Engagement Activity 2017
 
Description MRC Roadshow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Visited Comberton school where I and members of my group gave talks on careers in research and demonstrations of research software.
Year(s) Of Engagement Activity 2017
 
Description News coverage of JBC publication in MRC Network 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact A news article was published in MRC Network in response to a recently published paper in the Journal of Biological Chemistry. This raised awareness of recent research into the atomic structure of IKK-gamma and the overall implications of this research.
Year(s) Of Engagement Activity 2015
URL https://www.mrc.ac.uk/publications/browse/network-autumn-2015/
 
Description News coverage of JBC publication on MRC website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact A news article featured on the MRC website in response to a recently published paper in the Journal of Biological Chemistry. This raised awareness of recent research into the atomic structure of IKK-gamma and the overall implications of this research.
Year(s) Of Engagement Activity 2015
URL http://www.mrc.ac.uk/news/browse/cell-switch-discovered-that-could-shed-light-on-cancer/
 
Description Participation in MRC Festival of Science Open Day 2016 at MRC CU 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 60 sixth-form students from across 8 schools in Cambridge visited the MRC Cancer Unit on the afternoon of the 22nd of June, 2016 for an Open Day. All students, accompanied by their teachers, were given a tour of the enitre building with an opportunity for engaging with researchers about the state of the art in cancer research and gaining hands-on experience with setting up experiments. Talks about career opportunities and challenges associated with pursuing cancer research were also available to all attendees. The event sparked a great deal of interest and enthusiasm in students and teachers alike and we have had a request for this event to be continued. We will be pursuing a similar format of activities for the MRC Science Festival in 2017, but reach out to more number of schools, including those outside of Cambridge city perimeters.
Year(s) Of Engagement Activity 2016
URL https://mrccancerunit.wordpress.com/2016/07/06/inspiring-the-next-generation-of-cancer-researchers-t...
 
Description Participation in the University of Cambridge Science Festival (2015, 2016, 2017, 2018) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Cambridge Science Festival aims to reach out to the general public and communicate about the different aspects of science and research being undertaken at the University. It is a free event, over two weeks, with an excess of 270 events and more than 50000 attendees last year. As part of this, the MRC CU along with other departments from the BioMedical Campus organised a set of talks and activities on the BioMed Campus day of the Festival that were attended by over 2000 people from all walks of life - from young children and young adults to parents/carers and professionals. The Hall lab was part of the MRC CU team at this event. The event generated a lot of interest in cancer research, helped raise awareness about the importance of 'early' in cancer which is the mission of the MRc CU and also led to a lot of interest being generated in the MRC Festival of Medical Research which followed on later in the year.
Year(s) Of Engagement Activity 2015,2016,2017,2018
URL https://www.mrc-cu.cam.ac.uk/PublicEngagement/publicengagementhighlights
 
Description Talk at Hills Road Sixth form 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Gave an invited talk about my research program and careers in research to A-level students.
Year(s) Of Engagement Activity 2017
 
Description Think Computer Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Several schools attended a day of talks, demos and practical demonstrations aimed at engaging children with computer science. There was press coverage (BBC radio Cambridgeshire). Strong positive feedback from participating schools with > 90 % of pupils reporting that the talks and demos were interesting and informative, 82 % reporting that it had increased their interest in computer science, and 68 % stating that it had inspired them to learn how to code.
Year(s) Of Engagement Activity 2014
URL http://research.microsoft.com/en-us/um/cambridge/events/thinkcomputerscience/
 
Description Visit to AstraZeneca Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Invited to give a presentation, attend meetings and view facilities at AZ Cambridge by Drs Claus Bendtsen and Matt Bridgland-Taylor.
Year(s) Of Engagement Activity 2017