Identifying lung airway stem cells and understanding their cell fate decisions in the development of lung cancer.

Lead Research Organisation: University College London
Department Name: Unlisted

Abstract

Lung cancer is the leading cause of cancer death in the world. Cancers, such as breast, prostate and colorectal, have seen new principles and innovations in diagnostic testing and treatment strategies improve survival rates dramatically. These improvements have in part been due to improved diagnosis and treatment of pre-cancerous lesions, where the cancer has not fully developed or spread and remains treatable. As a research group based in the Rayne Institute Centre for Respiratory Research, University College London, we hope to identify cells involved in the generation of lung cancers and determine the factors within the cells that commonly lead to their development. It now appears that a normal cells behaviour can be converted into that of a cancer cell by the same messages, but uncontrolled, that govern the development of the lungs in the womb. We intend to investigate one particular candidate pathway termed the Wnt pathway, involved in lung development, that we believe is also involved in the development of early lung cancer lesions. Our investigations hope to identify the cells responsible for cancer development and the messages responsible for their abnormal behaviour, particularly in early cancer lesions and that this may lead to new therapeutic possibilities.

Technical Summary

Lung cancer is the leading cause of death due to neoplasia in the world. Cancers, such as breast, prostate and colorectal, have seen new principles and innovations in diagnostic testing and treatment strategies improve survival rates dramatically. These improvements have been partly due to improved diagnosis and treatment of pre-invasive lesions. Stem cell longevity within airways allows for the accumulation of the multiple genetic hits required for cancer formation. However the identification of these stem cells and markers for them has proved problematic. Identifying stem cells and their inappropriately regulated intrinsic and extrinsic molecular cues is vital in understanding lung cancer development and will direct future therapeutic strategies in targeting treatments to pre-invasive lesions.
Low retinoic acid receptor RAR ) expression is related to the development of squamous metaplasia. RA activity on RAR responsive promotors is potentiated by -catenin, a key signalling molecule in the Wnt pathway, while retinoids decrease signalling through the -catenin/TCF/LEF pathway by RARs competing with TCF/Lef for -catenin binding. Hence the reduction of RAR expression in lung epithelium may cause metaplastic differentiation through upregulation of -catenin/Tcf/Lef complex signalling.
The aim of my proposal is threefold.
1 To fully characterise normal lung airway stem cells.
2 To determine the effects of -catenin signalling on decisions of stem cell fate.
3 To examine -catenin expression in the human metaplasia - dysplasia - carcinoma-in-situ model of squamous carcinoma of the lung.
First I will use lineage marking experiments to investigate the full stem cell potential of keratin 14 positive cells in the upper trachea. Subsequently by expressing constitutively active -catenin or c-Myc (promoting -catenin signalling), or a dominant negative Lef1 (inhibiting -catenin signalling) in these putative stem cells, I will determine the effects of the transgene expression on cell behaviour. Finally I will investigate whether the -catenin signalling system is involved in the abnormal program of differentiation seen in the human metaplasia - dysplasia - carcinoma-in-situ model of squamous carcinoma of the lung. The identification of developmentally regulated pathways that are also active in cancer formation will provide important clues into the early developmental process of pre-invasive cancer formation and may direct future treatments in the prevention of lung cancer.

Publications

10 25 50
 
Description British Thoracic Oncology Group
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in advisory committee
Impact Directing National Meetings and advising on health documents
 
Description Department of Health policy on Mesothelioma Research
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guidance committee
Impact Directing future research funding
 
Description I sit on the national committee for invasive bronchoscopy.
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact nil yet
 
Description BLF Project Grant
Amount £101,000 (GBP)
Organisation British Lung Foundation (BLF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 04/2011
 
Description Biomedical Resarch Centre Funding, Strategic Grant
Amount £492,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Public
Country United Kingdom
Start 07/2009 
End 06/2012
 
Description CTAAC Clinical Trial Grant
Amount £700,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2016 
End 10/2022
 
Description ERS, Long Term Training Fellowship
Amount £40,000 (GBP)
Organisation European Respiratory Society (ERS) 
Sector Charity/Non Profit
Country European Union (EU)
Start 08/2008 
End 07/2009
 
Description European Research Society Fellowship
Amount £40,000 (GBP)
Organisation European Respiratory Society (ERS) 
Sector Charity/Non Profit
Country European Union (EU)
Start 08/2009 
End 07/2010
 
Description Johnson and Johnson Focussed Giving
Amount £120,000 (GBP)
Organisation Johnson & Johnson 
Sector Private
Country United States
Start 01/2006 
End 01/2009
 
Description MRC Clinical Training Fellowship
Amount £220,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description MRC Clinical Training Fellowship
Amount £240,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 09/2013
 
Description MRC Clinical Training Fellowship G0800465
Amount £240,000 (GBP)
Funding ID G0800465 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2007 
End 03/2011
 
Description MRC Clinical Training Fellowship G0900380
Amount £240,000 (GBP)
Funding ID G0900380 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description Project Grant
Amount £74,603 (GBP)
Organisation Roy Castle Lung Cancer Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2015
 
Description Project Grant
Amount £149,599 (GBP)
Organisation Roy Castle Lung Cancer Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2017 
End 09/2019
 
Description Project grant
Amount £146,955 (GBP)
Organisation Roy Castle Lung Cancer Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2016
 
Description Royal Society Newton International Fellowship
Amount £80,000 (GBP)
Organisation Royal Society and Department for International Development Network Grant 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2018
 
Description Training Fellowship
Amount £280,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Academic/University
Country United Kingdom
Start 02/2014 
End 01/2017
 
Description Wellcome Senior Fellowship in Clinical Sciences (Mesenchymal Stromal Cells as Therapeutic Vectors for Metastatic Cancer)
Amount £1,658,140 (GBP)
Funding ID 091730 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 09/2015
 
Title Human Lung Biopsies 
Description Cohort of biopsy material from rare pre-invasive lung tissue 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Contribution towards a pre-invasise gene atlas 
 
Description Cell therapy for lung fibrosis 
Organisation Johnson & Johnson
Country United States 
Sector Private 
PI Contribution I supervised a post doctoral worker delivering a combined cellular and gene therapy to attenuate lung fibrosis.
Collaborator Contribution JnJ funded a post doctoral worker for a project shortly after I received my Clinician Scientist Fellowship, largely because of the MRC award.
Impact JnJ funded a post doctoral worker for a project shortly after I received my Clinician Scientist Fellowship, largely because of the MRC award. Two Aguilar et al publications were produced.PMID: 19956603; PMID: 17363552
Start Year 2006
 
Description ESPRC Nano-technology Grand Challenge 
Organisation The Royal Institution of Great Britain
Country United Kingdom 
Sector Academic/University 
PI Contribution I have a post doctoral fellow setting up cancer models and delivering MSCs carrying the nano-particle therapeutics.
Collaborator Contribution Quentin Pankhurst (the cheif investigator) supplies nanoparticles and the MACH heating system enabling me to deliver a cellular therapy carrying nano-particle that can trate cancers through hyperthermia. Mark Lythgoe a co-applicant performs MRI imaging of these lesions.
Impact EPSRC Nanotechnology grand challenge grant 2009-2012. PMID: 19920196
Start Year 2007
 
Title Use of Nanoparticles for Cancer Treatment 
Description The use of combined mesenchymal stem cells and nanoparticles in the treatment of cancer 
IP Reference US20120010499 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact Further funding from Johnson and Johnson has been obtained
 
Description Press Conference 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact I gave a press conference after the publication of my paper describing the use of MSCs for meatastatic lung cancer. This generated articles in the Times, Telegraph, Mirror and Daily Mail. I appeared on BBC radio Five and the World Service. I appeared on the BBC TV London News, discussing the work.

The above led to a wide population seeing the work and a large response from the general public interested in the work.
Year(s) Of Engagement Activity 2008,2009
 
Description Radio Show 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Case Notes Radio Four Show on lung Cancer, BBC radio five live, BBC world service

I delivered my research finding to a wide audience.
Year(s) Of Engagement Activity 2009
 
Description Royal College lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact State of the Art Royal college lecture

Delivered the findings of my research to a general physician audience.
Year(s) Of Engagement Activity 2008
 
Description Scotland Royal College of Physicians 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact State of the Art lecture

Delivered the findings of my research to general physicians in Scotland
Year(s) Of Engagement Activity 2008