Cell Proliferation

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

Cancer is one of the leading causes of mortality in Britain and in the whole world. Cancer research is an especially complex issue, as what we call cancer is a set of more than 100 different diseases. In addition from the genetic perspective, every tumour presents more than 6 different genes altered. In this way, hundreds of genes have been proposed to be cancer genes. The prediction is that many other genes remain to be identified. Moreover, to really discern which genes are causing and which ones are just altered as a mere consequence of cancer, we have to identify the function of these genes.|The final goal of our laboratory is to identify novel cancer genes and understand how they work. This will be the basis for novel treatment, diagnostic and/or prognosis of cancer. |To this end, we use a simple approach. Using normal cells that we can culture, we introduce to them a collection of genes and aim to identify the ones that confer cancer-characteristics to normal cells. By testing randomly big collections of genes, our goal is to identify novel genes with a direct role in cancer. Also, the way in which we design our experiments implies that we detect only those genes which have a functional relation with cancer.

Technical Summary

The ultimate goal of our group is to identify novel genes involved in cancer and analyze how they are related with the genetic networks regulating cell proliferation. Normal cells have a limited ability to proliferate. When primary cells reach this limit or upon the expression of some oncogenes, they cannot growth anymore, suffering an irreversible growth arrest termed senescence.||Specifically our laboratory works in understanding senescence as it is a tumour suppressor mechanism that hinders tumour progression but also since we can use it as a model system, as often the genes identified in this way have a role in cancer or other human diseases. We use normal cells (different human and mouse cells of epithelial and fibroblast origin) and perform genetic screenings to identify genes regulating their lifespan. We use cDNA, shRNA and microRNA retroviral or lentiviral libraries in our screenings. As we already mentioned, we are interesting in identifying new genes or genetic elements regulating senescence and possibly impacting in cancer. Current experiments have identified novel candidates which a role in senescence, and we are performing genetic and molecular biology-based experiments to understand how they relate to the core pathways controlling senescence and oncogenesis.||In the past, using genetic screenings, we identified the role of glycolytic enzymes in senescence and cancer and how the Polycomb group (PcG) gene CBX7 modulates cellular lifespan by repressing the transcription of the Ink4a/Arf locus and therefore interfering with the Rb and p53 pathways. An area of continuous interest in our laboratory is to further understand the mechanism of action of CBX7 and which is its function under physiological and pathological conditions. We are pursuing that goals through the characterization of CBX7-interacting proteins that we have identified in yeast-2-hybrid screenings and by tandem affinity purification (TAP) followed by Mass Spectroscopy (MS). We are characterizing three interesting candidates flagged through those approaches. ||On the other hand, we have developed appropriate models through our collaboration with Scott Lowe (CSHL, NY, USA) to understand the role of CBX7 in cancer and in normal and pathological circumstances.

Publications

10 25 50
 
Description Gave evidence to the House of Lords Science Committee enquiry on healthy Ageing
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description AICR Project Grant (Identification of genes controlling replicative senescence in human epithelial cells and cancer)
Amount £210,206 (GBP)
Funding ID 08-0118 
Organisation Association for International Cancer Research 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2008 
End 03/2011
 
Description ARC Fellowship (Role of senescence in limiting prostate cancer progression)
Amount £22,000 (GBP)
Organisation International Agency for Research on Cancer (IARC) 
Sector Academic/University
Country France
Start 04/2009 
End 03/2010
 
Description BHF Centre for Excellent (main PI Sian Harding)
Amount £172,429 (GBP)
Funding ID WHCF_P47532 subproject 3 to P47352 (shared with Prof A. Fisher) 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2017
 
Description CRUK Project Grant (Identification and characterisation of microRNAs with oncogenic properties)
Amount £221,713 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2007 
End 12/2009
 
Description CRUK Project:Oncogene-induced senescence as a route to tumour suppressor discovery
Amount £129,021 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2006 
End 10/2009
 
Description EMBO LT fellowship
Amount £24,000 (GBP)
Organisation European Molecular Biology Organisation 
Sector Charity/Non Profit
Country Germany
Start 04/2009 
End 03/2010
 
Description EMBO LT fellowship
Amount £60,000 (GBP)
Organisation European Molecular Biology Organisation 
Sector Charity/Non Profit
Country Germany
Start 04/2013 
End 03/2015
 
Description EMBO Young Investigator Programme (Exploiting cellular senescence to identify novel cancer genes)
Amount £40,000 (GBP)
Organisation European Molecular Biology Organisation 
Sector Charity/Non Profit
Country Germany
Start 01/2009 
End 12/2011
 
Description FCT portuguese PhD fellowship
Amount £100,000 (GBP)
Organisation New University of Lisbon 
Department Foundation for Science and Technology
Sector Academic/University
Country Portugal
Start 10/2010 
End 12/2013
 
Description FCT, Project Grant, Identification of genes controlling senescence in mouse embryonic fibroblasts
Amount £90,000 (GBP)
Organisation New University of Lisbon 
Department Foundation for Science and Technology
Sector Academic/University
Country Portugal
Start 01/2007 
End 12/2010
 
Description Fundación Ramón Areces Fellowship (Regulation of Polycomb group gene expression)
Amount £45,000 (GBP)
Organisation Ramón Areces Foundation 
Sector Charity/Non Profit
Country Spain
Start 01/2007 
End 10/2008
 
Description Hammersmith Hospital Research Committee, Project Grant, MicroRNA expression profile associated with oncogene-induced senescence
Amount £9,980 (GBP)
Organisation Imperial College Healthcare NHS Trust 
Sector Hospitals
Country United Kingdom
Start 08/2006 
End 07/2007
 
Description MRC Centennary Awards
Amount £20,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 09/2013
 
Description MRC Developmental Gap Funding (Screening for small compounds modulating senescence)
Amount £122,894 (GBP)
Organisation MRC-Technology 
Sector Private
Country United Kingdom
Start 01/2010 
End 12/2011
 
Description MRC/BHF Cardiovascuular stem cell research strategic fund grant
Amount £125,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2010 
End 11/2013
 
Description MRC/BHF Cardiovascuular stem cell research strategic fund grant
Amount £125,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2010 
End 11/2013
 
Description MRCT development gap fund
Amount £155,273 (GBP)
Organisation MRC-Technology 
Sector Private
Country United Kingdom
Start 04/2016 
End 03/2018
 
Description marie curie fellowship
Amount £125,000 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Charity/Non Profit
Country Global
Start 04/2011 
End 03/2013
 
Description Animal models 
Organisation Cold Spring Harbor Laboratory (CSHL)
Country United States 
Sector Charity/Non Profit 
PI Contribution research
Collaborator Contribution research
Impact 17374722
 
Description Glycolysis 
Organisation University of Kyoto
Country Japan 
Sector Academic/University 
PI Contribution research
Collaborator Contribution research
Impact 17128414
 
Description Immunohistochemistry 
Organisation AIRC Foundation for Cancer Research in Italy
Department FIRC Institute of Molecular Oncology Foundation
Country Italy 
Sector Academic/University 
PI Contribution Analysis of gene expression in Cancer. Resulted in a Cell paper
Collaborator Contribution researchresearchresearch
Impact 18555777
 
Description Immunohistochemistry 
Organisation City University of New York (CUNY)
Country United States 
Sector Academic/University 
PI Contribution Analysis of gene expression in Cancer. Resulted in a Cell paper
Collaborator Contribution researchresearchresearch
Impact 18555777
 
Description Immunohistochemistry 
Organisation University of Lyon
Country France 
Sector Academic/University 
PI Contribution Analysis of gene expression in Cancer. Resulted in a Cell paper
Collaborator Contribution researchresearchresearch
Impact 18555777
 
Description JMJD3 
Organisation Cancer Research UK
Department Cancer Research UK London Research Institute (LRI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Research
Collaborator Contribution researchresearch
Impact 19451218
 
Description JMJD3 
Organisation Mount Sinai Hospital (USA)
Country United States 
Sector Hospitals 
PI Contribution Research
Collaborator Contribution researchresearch
Impact 19451218
 
Description Reprogramming 
Organisation Imperial College London
Department Institute of Reproductive and Developmental Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution research
Collaborator Contribution researchresearchresearchresearch
Impact 19696146
Start Year 2008
 
Description Reprogramming 
Organisation Mount Sinai Hospital (USA)
Country United States 
Sector Hospitals 
PI Contribution research
Collaborator Contribution researchresearchresearchresearch
Impact 19696146
Start Year 2008
 
Description Reprogramming 
Organisation St Jude Children's Hospital
Department Department of Surgery
Country United States 
Sector Hospitals 
PI Contribution research
Collaborator Contribution researchresearchresearchresearch
Impact 19696146
Start Year 2008
 
Description Reprogramming 
Organisation Wellcome Trust
Department Wellcome - MRC Cambridge Stem Cell Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution research
Collaborator Contribution researchresearchresearchresearch
Impact 19696146
Start Year 2008
 
Title SENOLYTIC COMPOUNDS 
Description The present invention relates to an agent for use in selectively killing one or more senescent cells, wherein said agent is selected from the following: a cardiac glycoside or alglycone, a focal adhesion kinase (FAK) inhibitor, an HMG-CoA reductase inhibitor, JFD00244, Cyclosporine, Tyrphostin AG879, Cantharidin, Diphenyleneiodonium chloride, Rottlerin, 2,3-Dimethoxy-1,4-naphthoquinone, LY-367,265, Rotenone, Idarubicin, Dequalintum chloride, Vincristine, Nitazoxanide, Nitrofurazone, Temsirolimus, Eltrombopag, Adapalene, Azacyclonol, Enoxacin and Raltegravir, and pharmaceutically acceptable salts thereof. Another aspect relates to compounds for use in treating or preventing a senescence- associated disease or disorder, and methods relating thereto. 
IP Reference WO2018215795 
Protection Patent application published
Year Protection Granted 2018
Licensed Commercial In Confidence
Impact Licensing is the most notable impact so far.
 
Description Interview Spanish television TVE for night nws 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact interview about science for the 9 news on Spanish TVE

Interest about science
Year(s) Of Engagement Activity 2010
 
Description Interview for BBC news website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Interview to BBC news to comment on a recent paper published by a group in the States

Audience noticed
Year(s) Of Engagement Activity 2011
 
Description Interview for Onda CEro spanish radio 
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 Interview about science and Spanish scientist abroad

general audience noticed
Year(s) Of Engagement Activity 2011
 
Description Interviews EMBO YIP award 
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 Several interviews to Spanish Media (newspapers Vanguardia, Publico; News Agencies: Efe; Radios: Radio Nacional) regarding the award of the EMBO YIP

It was all over the press and highlighted the CSC and the funding of the MRC in making the science progress. Also gave opportunity to highlighht our research
Year(s) Of Engagement Activity 2008
 
Description Press Release CXCR2 paper 
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 Press release about our 2008 Cell paper on the role of CXCR2 in Senescence. It was also picked by the MRC in its 2008/2009 annual brochure

Disseminate the importance of research
Year(s) Of Engagement Activity 2008