Cellular plasticity and senescence at the origin of lung cancer

Lead Research Organisation: University of Cambridge
Department Name: Oncology

Abstract

Cancer is a leading cause of morbidity and mortality worldwide. Every year some 15 million new cancer cases are diagnosed, and over 8 million people succumb annually to a variety of cancer types. Some 1.5 million of the former deaths are directly assigned to lung cancer, making it the most common cause of cancer-related fatality. Despite the remarkable efforts in lung cancer research of the last decades we yet ignore the underlying mechanisms promoting malignant transformation. Consequently, the available tools for lung cancer early diagnosis as well as the therapeutic approaches at hand are not good enough to tackle this disease. Most of the lung cancer cases escape diagnosis until they are at an advanced stage, which results in around 85% of patients having a 5-year mortality from first diagnosis.

Identification of the cell that initiates lung cancer is still a controversial issue and it remains unknown to what extent it determines tumour phenotype. It has been speculated that different lung tumour subtypes arise from distinct cells of origin localised in defined microenvironments. It has also been proposed that stem/progenitor cells may originate lung cancer due to their prolonged lifespan and capacity for self-renewal and differentiation. In the case of solid tumours like lung cancer, however, where the identification of cancer stem cells or progenitor cells relies on the expression of surface markers, it is unclear whether tumours follow a stochastic or a hierarchical growth. A satisfactory model(s) elucidating lung cancer initiation and tumour heterogeneity is thus yet to be verified. Evidence recently obtained in different tumour models, including glioblastomas, pancreatic and intestinal cancers, showed that the cell of origin is a differentiated cell that after exposition to diverse sources of damage undergoes de-differentiation and acquires a premalignant "plastic state" that initiates cancer. We will test in this proposal how cellular de-differentiation affects lung cancer initiation and progression in a microenvironment of damage and/or oncogenic stress.

Cellular senescence is a defence mechanism that occurs when a single cell is afflicted by different types of damage or stress, including oncogenic stress. Usually, these cells arrest and divide no more, and are subsequently eliminated by the immune system. Senescent cells accumulate in premalignant lesions, including lung adenomas, where senescence is a defining feature. Senescent cells can however implement in different tissues a complex secretory phenotype (termed SASP) that includes pro-inflammatory and pro-tumorigenic factors when they are accumulated and not cleared, which may in turn promote cancer. Based on our preliminary results, we hypothesize that senescent cells may produce through the SASP a maladaptive gain of plasticity in nearby differentiated cells favouring lung cancer initiation. In this regard, we have observed in mouse lungs a close association between senescent cells and cells expressing pluripotency markers upon damage or oncogenic stress. We will determine whether senescence-induced plasticity is a potent oncogenic promoter in the lung.

We will employ mouse models where lung cancer has been induced either genetically or chemically, strains to manipulate cellular senescence and to induce de-differentiation processes, and lineage tracing approaches. We will acquire supporting data in a clinical oncology context through the analysis of human lung tissue samples. The overall purpose of this project is to achieve a better understanding of the mechanisms and processes contributing to lung cancer initiation at the cellular level, still a formidable challenge in oncology. Such fundamental knowledge is crucial to develop more efficient diagnostic tools, especially for the early detection of lung cancer, and novel therapeutic interventions and treatment modalities, therefore meeting an already existing and demanding clinical need.

Technical Summary

Our main objective is a better understanding of the mechanisms and processes that lay at the origin of lung cancer. In other tumour models, it is known that, upon damage and/or oncogenic stress, differentiated cells may undergo de-differentiation (gain of plasticity) acquiring malignant phenotypes. Since cell senescence is a response to damage and stress, and senescent cells can secrete pro-inflammatory and pro-tumorigenic factors, we hypothesize these cells can also induce in nearby cells de-differentiation processes favouring lung cancer initiation.
Our specific aims are:
(i) To induce lung de-differentiation processes upon damage (urethane treatment) and/or oncogenic stress (K-Ras activation). To do so, we will employ a regrogrammable mouse model transiently expressing the four Yamanaka factors. We will determine whether reprogramming-induced de-differentiation is an oncogenic promoter.
(ii) To capture early tumour cells expressing transiently or stably de-differentiation markers by using a lineage tracing mouse strain and FACS approaches. Cells will be subjected to RNAseq analyses and epigenetic techniques such as chromatin immunoprecipitation.
(iii) To address the interplay between cell senescence and de-differentiation processes during lung tumorigenesis. Senescence will be manipulated both genetically and chemically during lung cancer initiation. Lineage tracing approaches will allow us to perform longitudinal studies on the activation of pluripotency markers and how it relates to senescence. We will determine if senescence-induced plasticity is an important oncogenic promoter.
(iv) To identify factors secreted by senescent cells able to induce de-differentiation of nearby cells and/or malignant transformations. Microdissected sections of tumours from control and senescence-manipulated mice will be subjected to gene expression and protein arrays. Conditioned media from cultured senescent cells will be subjected to SILAC analyses.

Planned Impact

The Pathways to Impact Assessment, the potential beneficiaries of this project on lung cancer are multiple and diverse reflecting the fact that it aims to deliver knowledge and know-how at three fundamental levels: molecular mechanisms, cell processes and pathological disorders.

Our expected advancements on the molecular front will be beneficial to:
- molecular biologists and cancer researchers, through the development of new techniques for the isolation of tumour precursor cells;
- oncologist consultants, which will have at hand a new tool to detect alterations during cancer initiation thanks to the characterisation of gene expression profiles and epigenetic changes of cancer precursor cells;
- drug discovery programmes, after the identification of new drugable targets in lung cancer initiation.

Our progress on better understanding the role of cellular senescence and gain of cellular plasticity processes will be very useful for cell biologists interested in cancer initiation, cell senescence and plasticity, stem/progenitor cells and cell reprogramming. Satisfactory results attained within this proposal may provide us with the grounds for the diversification of our own research towards the development of nanoparticles to specifically target senescent cells in lung premalignant lesions which in turn could eventually be of some use for translational researchers and engineers working in imaging and biomarker approaches.

On the pathological front, a better understanding of lung cancer initiation is crucial to develop novel tools for early detection the design of more efficient therapeutic interventions. In the former context Dr Robert Rintoul, Lung Cancer Lead Clinician at Papworth Hospital and Director of the Clinical Trials Unit, will directly benefit thanks to our already established collaboration. Given that senescence is associated with multiple cancers and premalignant lesions, the Cambridge Cancer Centre will directly benefit from our proposal. This includes Prof Sir Bruce Ponder, former director of the CRUK Cambridge Institute, through an ongoing collaboration. Cell senescence also operates in a multitude of chronic pathologies making our proposal thus of interest to a broader research community operating in basic and translational projects both in the UK and overseas.

Publications

10 25 50
 
Description International Summer School - Organisation of a Networking Activity as Scrum Master
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact International Summer School Date: Monday 15th July 2019 - Thursday 18th July 2019 Venue: Robinson College, Grange Road, Cambridge CB3 9AN, UK We organised the first international summer school on discovery and development of diagnostics for the early detection of cancer. The summer school was aimed at those who are developing new technologies and interventions for the early detection of cancer and those who are interested in exploring this rapidly expanding and exciting field and was open to academic, corporate and student delegates. In July 2020 the inaugural International Early Detection Summer School, supported by the CRUK Cambridge Centre Early Detection Programme and the International Cancer Early Detection (ICED) Alliance, was held in the beautiful surroundings of Robinson College, Cambridge. The major theme of 'Discovery and Development of Diagnostics for Early Detection of Cancer' was delivered by world-class international Faculty, and the diagnostic development themes were explored more deeply in small groups through an interactive Team Activity. This was a truly international summer school with 60 delegates attending from 32 different institutions across 7 countries, including attendees from other ICED Alliance member centres, such as University of Manchester and UCL. The international faculty and speakers consisted of world leaders from a diverse range of specialities, including regulatory authorities, international certification bodies, large and small biotechnology companies, and academics focussed on cancer early detection. Delegates from the inaugural International Early Detection Summer School listening to the introductory talk from Prof Rebecca Fitzgerald, on the need for Cancer Early Detection and a case study of the CytoSpongeTM platform for oesophageal neoplasms, moderated by Dr Sarah Bohndiek (co-leader of the CCC Early Detection Programme). The Summer School provided insights from experts with real-world experience in developing diagnostics and key insights on the pathway to implementation. The speakers covered topics ranging from the need for cancer early detection and emerging technologies, to case-studies and clinical trials from successful pioneers in the field of Early Detection, including regulation and policy challenges of new screening and diagnostic tools. Talks from Rebecca Fitzgerald (CytospongeTM), Nickolas Papadopoulos (CancerSEEK), Barry Berger (Cologuard®), Henrik Winther (IMMray TM), and Attilla Lorincz (Qiagen/Digene HPV test) were among the success stories that covered development from concept to clinical trials and considerations for implementation of cancer early detection in a variety of malignancies. Stephen Quake (Stanford) and Chris Contag (Michigan State) covered exciting new technologies for cancer detection, ranging from molecular analysis to optical imaging. While real-world impact and implementation was covered from a broad range of perspectives by Anne Mackie (Public Health England), Maroeska Rovers (Radboud), Alberto Gutierrez (former FDA Director), Sian Taylor-Phillips (Warwick) and Robyn Meurant (NSF International). Considerations for the design of clinical trials and early detection of cancer in primary care were expertly covered by Peter Sasieni (King's College London) and Fiona Walter (Cambridge/CanTest). The balanced programme concluded with a final session of speakers covering the specific challenges for development in this area, both from a regulatory perspective and considerations for the societal impact of cancer early detection. Talks from Lynette Reid (Dalhousie), Stephen John (Cambridge) and Maryon McDonald (Cambridge), actively moderated by Stuart Hogarth (Cambridge), one of the co-organisers of the Summer School, gave much food for thought on the potential impacts of early detection and the importance of clarity in communicating with target 'testing' populations, as well as the need to ensure that any new early detection test strikes the correct balance between benefits and harms, to realise the core goal of 'timely detection' of lethal cancers to improve survival rates. Throughout the four-day Summer School five delegates trained by Carl Yamashiro (Arizona State University), including Wendy Alderton, Charlie Massie and Daniel Munoz-Espin (CCC Early Detection Programme), Valerie Sills (PHPC, Cambridge), and Cindy Azevedo (Arizona State University), took part in a team activity to work through the stages of developing an early detection test. Working in small groups after each session, delegates covered in greater depth the development process starting from concept and ideation, through considerations for specific technologies, practicalities for implementation, quality systems, assessing competition and IP, regulation, reimbursement, marketing, and final commercialisation. Using a tailored agile development programme, implemented together with the team from Arizona State University, delegates were mentored through the complexities and considerations for realising cancer early detection diagnostics. The team development activity culminated in a series of short presentations at the end of the Summer School and the award of the first International Early Detection Prizes! Team activity session. Working in small groups, delegates explored the key considerations for the development of cancer early detection tests. Using an agile development process and short 'sprints', facilitated by 'scrum masters' (in this case, Daniel Munoz-Espin). The feedback for the event was very positive, with 100% of delegates agreeing that the course was well organised and met the key objectives for the topics of Developing Diagnostics for Cancer Early Detection. We had very positive feedback from delegates: "Amazing range and level of speakers" "Cytosponge, CancerSEEK, Quake, Immunovia, Cologard were amazing talks. Learned a lot about science, regulatory, clinical validation, societal elements" "Excellent range of talks, great presenters across the board" "It was a really good multidisciplinary event and I enjoyed having the opportunity to network with researchers that are tackling the early detection problem form such different viewpoints." In conclusion, the first International Early Detection Summer School brought together an outstanding team of senior faculty, speakers, associates, and delegates from multiple international institutions sharing the vision of increasing survival from cancer and improving quality of life through early detection and intervention. We are already planning the next International Early Detection Summer School, so watch this space and look out for email alerts to make sure you don't miss out on the next Summer School!
URL https://www.earlydetectioncambridge.org.uk/news-events/international-summer-school
 
Description Lectures on Cancer Biology at University of Cambridge
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact I gave a Lecture for the training of PhD students entitled "Imaging techniques and novel tools for cancer early detection and intervention" on the 8th March 2018 at 9.30 am in Lecture Theatre 2 of the Clinical School, University of Cambridge. It was aimed at reinforcing the training and educational developments for postgraduates.
URL https://crukcambridgecentre.org.uk/content/lectures-cancer-biology-and-medicine-2017-18
 
Description Member of the CRUK Cambridge Centre Early Detection Programme Steering Committee
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact The International Alliance for Cancer Early Detection (ACED) is a science-led, collaborative investment that will support the early detection of cancer research. Launched in 2019, representing up to £55 million of investment over 5 years, this initiative brings together outstanding UK and US Centres to foster collaboration (University of Cambridge, Manchester University, UCL, OHSU and Canary Foundation), infrastructure development and training across the Alliance and for the wider early detection research community. ACED in Cambridge Led by Professor Rebecca Fitzgerald, the Cambridge ACED member centre is leveraging the success of its Early Detection Programme to bring world-class facilities and early detection expertise to the wider Alliance. Central to this is the development of ACED Clinic Cambridge, which will provide Alliance members with the resources and infrastructure required to conduct first-in-human clinical testing of novel diagnostics and imaging devices. We are dedicated to training, development and multidisciplinary collaboration: we hosted the first International ACED Summer School in 2019, are funding three PhD studentships and are actively supporting the development of collaborations across the Alliance. Click here for details on the next ACED Summer School.
URL https://www.earlydetectioncambridge.org.uk/about/people/steering-committee
 
Description Dissecting the role of the senescent secretome in tumorigenesis. CRUK-OHSU Early Detection Project Award.
Amount £250,000 (GBP)
Funding ID C62187/A26989 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2019 
End 12/2020
 
Description La Caixa Foundation Fellowship
Amount £31,200 (GBP)
Organisation Fundacio La Caixa 
Sector Charity/Non Profit
Country Spain
Start 10/2017 
End 09/2019
 
Description Royal Society Research Grants
Amount £15,000 (GBP)
Funding ID RDAG/435 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 02/2018
 
Title Construction of vectors to generate novel mouse models to lineage trace senescent (p16-positive and p21-positive) cells 
Description Generation of mouse p16 and p21 gene targeting vectors to generate mouse models to lineage trace senescent (p16-positive and p21-positive) cells: P16 Donor Vector: P16 5'arm-IRES-frt-STOP-frt-mKATE2-2A-CreERT2-loxP-hPGK-blasticidin-loxP-3'arm P21 Donor Vector: P21 5'arm-IRES-frt-STOP-frt-mKATE2-2A-CreERT2-loxP-hPGK-blasticidin-loxP-3'arm 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2019 
Provided To Others? No  
Impact Not yet, in progression. 
 
Title Galacto-Conjugated Navitoclax. 
Description We have developed and validated a novel prodrug with broad-sprectrum senolytic activity, namely Galacto-conjugated Navitoclax (Gal-Nav). Gal-Nav allows a therapeutically-relevant activity in combination with senescence-inducing chemotherapy (e.g Palbociclib and Cisplatin) in different in vivo models of cancer: (i) Orthotopically transplanted murine lung adenocarcinoma cells and (ii) tumour xenograft models of human Non Small Cell Lung Cancer (NSCLC). Our in vitro and in vivo results show that concomitant treatment of senogenic chemotherapies and senolytics significantly improve the therapeutic outcomes of the monotherapies alone and results in reduced toxicities. 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? Yes  
Impact Targeting cellular senescence is emerging as a novel and promising therapeutic strategy for many diseases. Our work demonstrates the following three points: • We describe and validate the use of galacto-conjugated navitoclax as a prodrug with broad-spectrum senolytic activity in a variety of cellular models. • Galacto-conjugated navitoclax allows therapeutically-relevant activity in combination with senescence-inducing chemotherapy (cisplatin) in two in vivo models of lung carcinogenesis: Orthotopically transplanted murine lung adenocarcinoma cells and in a tumour xenograft model of human NSCLC. • Importantly, galacto-conjugation has the important advantage of reducing navitoclax-induced platelet apoptosis (thrombocytopenia), which limits the use of BCL-2 inhibitors in the clinic (currently in clinical trials). We regard this as a major technical advance with potential wide therapeutic applications in medicine. 
 
Title Gene expression profiles (RNAseq) of senescent cells and lung cancer cells 
Description We have performed whole transcriptome shotgun sequencing (RNAseq) to analyse human lung cancer cells (A549) undergoing different types of therapy-induced senescence (cisplatin, docetaxel and palbociclib-based). In addition, we have analysed the transcriptome of recipient human lung cancer cells (A549) exposed to different senescent secretomes. This will allow us to have a better understanding of the pro-tumorigenic (or pro-senescent) effects of the senescent secretome. These data will be further completed by using models of oncogene-induced senescence, which may represent more accurately the early phases of lung carcinogenesis, and by developing 3D cultures based on organoids. Databases will be shared at the time our results are submitted to a peer-reviewed research journal for publication, and also in international conferences. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? No  
Impact The development of tumour organoids in our laboratory may be a good replacement method allowing us to reduce the numbers of mice. We are currently setting up this novel approach in collaboration with Dr Joo-Hyeon Lee (WT Cambridge Stem Cell Institute). 
 
Title Human Tissues Samples 
Description Collection of human tissue samples of lung tumours, lung fibrosis and other pulmonary pathologies 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? No  
Impact The histological analysis of human tissue samples were used in a collaboration with Dr Ana O'Loghlen (Blizard Institute, London): Borghesan et al. Cell Reports 2019. 
URL https://www.sciencedirect.com/science/article/pii/S221112471930734X?via%3Dihub
 
Title Proteomics Analyses of Cell Membrane Proteins in Chemotherapy-Treated Lung Cancer Cells 
Description We are screening surface membrane proteins that are specifically or preferentially expressed in senescent cells with the aim of identifying senescence targetable biomarkers. The proteins that we are studying were identified in an initial proteomics analysis in collaboration with Prof Paul Lehner (CMIR, University of Cambridge). We will first confirm the overexpression of the identified protein/s in senescent cells, and study the effects of inhibiting or manipulating the protein expression. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? No  
Impact We performed a proteomic TMT-based analysis of cisplatin-induced senescent lung cancer cells in order to elucidate differences in the expression of proteins between senescent cells and their control counterparts. We conducted the biotinylation of proteins, biochemically labeling and protein separation of membrane and intracellular compartments, and performed a mass spectrometry screening. Preliminary analysis of the results shows differences on the protein levels and types between senescence and control cells. Due to the absence of universal biomarkers of senescent cells, the identification of cell surface (targetable) biomarkers is crucial for the development of novel and more specific senolytic, senomorphic and detection tools for senescent cells. There is a huge excitement with this field because of the recent realisation that cellular senescence is causative in multiple diseases in humans (reviewed in Muñoz-Espín D & Serrano M, Nat Rev Mol Cell Biol 2014), and hence senescent cells are an emerging target of a wide variety of age-related disorders (reviewed in Pérez-Mancera PA et al., Nat Rev Cancer 2014; Childs BG et al., Nat Rev Drug Disc 2017; Soto-Gamez et al., Drug Discovery Today 2017; Ovadya Y & Krizhanovsky V, JCI 2017; Gonzalez-Meljem JM et al., BJC 2018). Importantly, the elimination of senescent cells by genetic and pharmacological agents results in an increased healthspan and lifespan in mice (Baker DJ et al., Nature 2016; Xu M et al., Nat Med 2018). Even more, eradication of senescent cells not only ameliorates the pathological manifestations but, also, in some cases reverts the disease progression and contributes to tissue regeneration. Therefore, the development of novel tools to manipulate cellular senescence has an enormous potential in multiple clinical applications. 
 
Description Cellular senescence and mouse models 
Organisation Institute for Research in Biomedicine (IRB)
Country Spain 
Sector Academic/University 
PI Contribution We provide expertise in the role of cellular senescence in lung disorders, including lung cancer and pulmonary fibrosis. We also facilitate access to data related to the senescent secretome and transcriptomics analyses.
Collaborator Contribution Prof Manuel Serrano provides expertise on cellular senescence and reprogramming, intellectual input, and provision of some relevant mouse models, including: - p53KO and p16ArfKO mice. - Reprogrammable mouse (OSKM inducible, expressing the 4 Yamanaka factors in a transient manner).
Impact Recent publication of a Research Article: Muñoz-Espín D*, Rovira M, Galiana I, Giménez C, Lozano-Torres B, Paez-Ribes M, Llanos S, Chaib S, Muñoz M, Ucero AC, Garaulet G, Mulero F, Dann S, VanArsdale T, Shields DJ, Bernardos A, Murguía JR, Martínez-Máñez R, Serrano M*. A versatile drug delivery system targeting senescent cells. EMBO Mol Med. 2018; 10:e9355. (* Corresponding authors) doi: 10.15252/emmm.201809355. Patent: European Application Number: EP17382901.1. Title: Therapeutic Nanoparticles. Applicant: Spanish National Cancer Research Centre and Polytechnic University of Valencia. Inventors: Manuel Serrano, Daniel Muñoz, Miguel Rovira, Andrea Bernardos, Irene Galiana, Beatriz Lozano, Ramón Martínez, Félix Sanceón
Start Year 2018
 
Description Clinical oversight 
Organisation Cambridge University Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We contribute our expertise in cellular senescence and mouse models of lung carcinogenesis
Collaborator Contribution Dr Gary J Doherty (Oncologist and Respiratory Consultant) provides additional programme oversight and clinical lead in lung oncology.
Impact Experimental designs of preclinical studies in order to have relevance in clinical settings.
Start Year 2019
 
Description Consortium on Cellular Senescence - H2020-MSCA-ITN-2020-ENIGMAS 
Organisation Queen Mary University of London
Department Blizard Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution This is an European Network of Innovative Groups for research into the mechanisms of aging. The Consortium involves: 1. Queen Mary University of London. (Dr Cleo Bishop). 2. University of Cambridge. (Prof Masashi Narita). 3. Technische Universitaet Dresden (Germany). (Dr Maximina Yun). 4. Elvesys. (Dr Jessica Ayache, Dr Julia Sepulveda). 5. Universitaetsmedizin Göttingen (Germany). (Prof Argyris Papantonis). 6. Academisch Ziekenhuis Groningen (The Netherlands). (Dr Marco Demaria). 7. Institute for Research in Biomedicine, Barcelona (Spain). (Prof Manuel Serrano). 8. Ethnic Idryma Erevnon. (Dr Efstathios Gonos). 9. Institut Pasteur. (Dr Han Li). 10. Senolytic Therapeutics SL. (Dr Tim Cash). 11. Weizmann Institute of Science. (Dr Valery Krizhanovsky).
Collaborator Contribution Targeted clearance of senescent cells offers a new landscape through which to tackle the increasing fiscal and societal burden related to our growing ageing population, and a fresh approach to address the H2020 Societal Challenges of healthy ageing. However, fundamental challenges must be over come to realise the potential of senotherapies. We need: - new strategies for detecting and dissecting senescence mechanisms at the single-cell level; - an understanding of the temporal dynamics of senescence cell accumulation and the consequences of senescent cell elimination in disease; - and proof-of-concept therapeutic tools to detect and target senescent cells. In response to these overarching EU needs, we have built ENIGMAS (European Network of Innovative Groups for research into the Mechanisms of Ageing and Senescence). We are a network of leading senescence groups united with industrial and commercial stakeholders to create a multidisciplinary, cross-sectoral and transnational network to address the urgent training needs within the field. Our mission is to train the first breed of dedicated Senescence and Ageing experts equipped with a unique blend of transferable and entrepreneurial expertise. Our proposed training platform links senescence, ageing and diseases of ageing with core skills (cell and molecular biology, in vitro and in vivo models, start-of-the-art imaging) and key emerging transformative techniques (single cell genomics, proteomics, tissue engineering) and transformative technologies (nanotechnology using our patented nanoparticle delivery system and innovative microfluidics) to develop a new generation of senescence experts that can think and communicate across disciplines and sectors. Throughout the training programme, our ESRs will work at the cutting-edge of inter-sectoral technology transfer with preclinical application and future commercialisation potential.
Impact For the moment, we are at an initial stage of collaboration and have applied for H2020-MSCA-ITN-2020 (Marie Sklowdoska-Curie Innovative Training Networks). Proposal Acronym: ENIGMAS
Start Year 2019
 
Description Generation of mouse models for lineage tracing in lung carcinogenesis and tumour organoids 
Organisation Wellcome Trust
Department Wellcome - MRC Cambridge Stem Cell Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We contribute the construction of a vector to generate a novel mouse model for lineage tracing of p16-positive cells and another one for lineage tracing of p21-positive cells.
Collaborator Contribution Dr Joo-Hyeon Lee provides her expertise in lineage tracing, stem cells, and generation of lung tumour organoids.
Impact Future generation of novel mouse models for lineage tracing in lung carcinogenesis and novel tools based on tumour organoids.
Start Year 2018
 
Description Human lung tissue samples 
Organisation Papworth Hospital NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We contribute our expertise in cellular senescence and mouse models of lung carcinogenesis
Collaborator Contribution Dr Robert Rintoul (Respiratory Consultant) provides programme oversight and clinical lead in lung oncology. Dr Doris Rassl (Pathologist) provides the laboratory with human lung tissue samples and histology analysis.
Impact Validation of results obtained in mouse models of lung carcinogenesis with human tissue samples.
Start Year 2018
 
Description Lung cancer and mouse models 
Organisation Spanish National Cancer Research Center
Country Spain 
Sector Public 
PI Contribution We provide expertise on the role of cellular senescence in lung carcinogenesis.
Collaborator Contribution Prof Mariano Barbacid provides expertise on lung cancer and provision of mouse models: - FSF-KrasG12V - LSL-KrasG12VBgeo
Impact Generation of novel in vivo models to study lung carcinogenesis.
Start Year 2018
 
Description Reprogramming and cellular plasticity 
Organisation Galician Healthcare Service
Country Spain 
Sector Hospitals 
PI Contribution We contribute our expertise in cellular plasticity in lung carcinogenesis
Collaborator Contribution Dr Manuel Collado provides expertise in cellular reprogramming and cancer stemness. He is also an expert in cellular senescence.
Impact We have complementary models for lung carcinogenesis and reprogramming. We are designing multiple experiments in parallel and thinking in a future joint publication as a result of our strong interconnection.
Start Year 2019
 
Description Suicide mouse model to eradicate senescent cells 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution We contribute our expertise in cellular senescence and its association with lung carcinogenesis.
Collaborator Contribution Dr Juan Pedro Martinez-Barbera provided a novel mouse model to conditionally eradicate senescent (p16-positive) cells.
Impact Generation of novel mouse models to study lung carcinogenesis.
Start Year 2018
 
Description Annual Early Detection Symposium at CRUK Cambridge Institute 2019- Poster Presentation - Estela Gonzalez-Gualda 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Poster presentation on the effects of chemotherapy-induced senescence in lung cancer progression.
Year(s) Of Engagement Activity 2019
URL https://www.earlydetectioncambridge.org.uk/news-events/news/cruk-cambridge-centre-early-detection-pr...
 
Description Annual Early Detection Symposium at CRUK Cambridge Institute 2020- Poster Presentation - Zhenguang Zhang 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Poster presentation on the interplay between cellular reprogramming and lung cancer.
Year(s) Of Engagement Activity 2020
URL https://www.earlydetectioncambridge.org.uk/news-events/events/early-detection-programme-5th-annual-s...
 
Description Biological theories for rejuvenation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact About 300 respiratory consultants attended a debate on lung disease and ageing (invited by Dr Alvar Agusti. Neumochiesi 8th Edition. Real Fabrica de Tapices, Madrid, Spain). I gave a talk on biological theories for rejuvenation and participated in an open discussion.
Year(s) Of Engagement Activity 2018
URL https://www.actasanitaria.com/wp-content/uploads/2018/10/Programa-cient%C3%ADfico-Neumochiesi-2018.p...
 
Description Biological theories for rejuvenation - CHIESI RESPIRATORY SYMPOSIUM 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact About 350 respiratory consultants attended a debate on lung disease and ageing (invited by Dr Julio Delgado. ESPACIO ASMA 8th Edition. Hotel Melia Alicante, Alicante, Spain. I gave a talk on biological theories for rejuvenation and participated in an open discussion.
Year(s) Of Engagement Activity 2019
URL https://www.alicantecongresos.com/es/node/383
 
Description CRUK Engagement Event in Chelmsford (UK) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Almost 100 people, including supporters, charitable donors, and general public attended an engagement event organised by CRUK (Dr Helen Dowding, Research Engagement Manager) and the Cambridge Cancer Centre Early Detection Programme. As part of the the Early Detection Programme, my colleagues and I presented some talks on early cancer biology and novel tools for early detection in the Essex Country Cricket Club (Chelmsford, UK).
Year(s) Of Engagement Activity 2018
 
Description CRUK International Symposium at CRUK Cambridge Institute "Radical Approaches to Cancer Prevention"- Poster Presentation - Estela Gonzalez-Gualda 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Poster presentation on the impact of chemotherapy-induced senescence in lung cancer progression.
Year(s) Of Engagement Activity 2019
URL https://www.immunology.cam.ac.uk/immunologycinferences/NonCINEvents/cruk-cambridge-institute-interna...
 
Description Cambridge Science Festival - CRUK Cambridge Centre Early Detection Programme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The Science Festival provides the public with opportunities to explore and discuss issues of scientific interest and concern and to raise aspirations by encouraging young people to consider a career in science, technology, engineering or mathematics. Each year, the Festival welcomes visitors to hundreds of events and receives extensive national and local media coverage. Over 170 event coordinators organise talks, interactive demonstrations, hands-on activities, film showings and debates with the assistance of around 1,000 staff and students from departments and organisations across the University and research institutions, charities and industry in the eastern region. In addition, over 150 people volunteer their time to act as stewards to ensure visitors have a safe and enjoyable Festival experience.

We prepared an activity on the Early Detection of Lung Cancer, consisting in a video game that we created to target precancerous cells, a pinball with "drug-delivery balls" to target tumours, and an activity with a model of the human lung to detect early lesions by fluorescence techniques.
Year(s) Of Engagement Activity 2019
URL https://www.sciencefestival.cam.ac.uk
 
Description International Cellular Senescence Association (ICSA) Conference in Athens 2019 - Poster Presentation - Estela Gonzalez-Gualda 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Presentation of a poster on the impact of chemotherapy-induced senescence in lung cancer progression.
Year(s) Of Engagement Activity 2019
URL https://www.icsa2019-athens.gr
 
Description International Summer School - Organisation of a Networking Activity as Scrum Master 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact International Summer School

Date: Monday 15th July 2019 - Thursday 18th July 2019
Venue: Robinson College, Grange Road, Cambridge CB3 9AN, UK

We organised the first international summer school on discovery and development of diagnostics for the early detection of cancer. The summer school was aimed at those who are developing new technologies and interventions for the early detection of cancer and those who are interested in exploring this rapidly expanding and exciting field and was open to academic, corporate and student delegates.

In July 2020 the inaugural International Early Detection Summer School, supported by the CRUK Cambridge Centre Early Detection Programme and the International Cancer Early Detection (ICED) Alliance, was held in the beautiful surroundings of Robinson College, Cambridge. The major theme of 'Discovery and Development of Diagnostics for Early Detection of Cancer' was delivered by world-class international Faculty, and the diagnostic development themes were explored more deeply in small groups through an interactive Team Activity.

This was a truly international summer school with 60 delegates attending from 32 different institutions across 7 countries, including attendees from other ICED Alliance member centres, such as University of Manchester and UCL. The international faculty and speakers consisted of world leaders from a diverse range of specialities, including regulatory authorities, international certification bodies, large and small biotechnology companies, and academics focussed on cancer early detection.

Delegates from the inaugural International Early Detection Summer School listening to the introductory talk from Prof Rebecca Fitzgerald, on the need for Cancer Early Detection and a case study of the CytoSpongeTM platform for oesophageal neoplasms, moderated by Dr Sarah Bohndiek (co-leader of the CCC Early Detection Programme).

The Summer School provided insights from experts with real-world experience in developing diagnostics and key insights on the pathway to implementation. The speakers covered topics ranging from the need for cancer early detection and emerging technologies, to case-studies and clinical trials from successful pioneers in the field of Early Detection, including regulation and policy challenges of new screening and diagnostic tools.

Talks from Rebecca Fitzgerald (CytospongeTM), Nickolas Papadopoulos (CancerSEEK), Barry Berger (Cologuard®), Henrik Winther (IMMray TM), and Attilla Lorincz (Qiagen/Digene HPV test) were among the success stories that covered development from concept to clinical trials and considerations for implementation of cancer early detection in a variety of malignancies. Stephen Quake (Stanford) and Chris Contag (Michigan State) covered exciting new technologies for cancer detection, ranging from molecular analysis to optical imaging. While real-world impact and implementation was covered from a broad range of perspectives by Anne Mackie (Public Health England), Maroeska Rovers (Radboud), Alberto Gutierrez (former FDA Director), Sian Taylor-Phillips (Warwick) and Robyn Meurant (NSF International). Considerations for the design of clinical trials and early detection of cancer in primary care were expertly covered by Peter Sasieni (King's College London) and Fiona Walter (Cambridge/CanTest). The balanced programme concluded with a final session of speakers covering the specific challenges for development in this area, both from a regulatory perspective and considerations for the societal impact of cancer early detection. Talks from Lynette Reid (Dalhousie), Stephen John (Cambridge) and Maryon McDonald (Cambridge), actively moderated by Stuart Hogarth (Cambridge), one of the co-organisers of the Summer School, gave much food for thought on the potential impacts of early detection and the importance of clarity in communicating with target 'testing' populations, as well as the need to ensure that any new early detection test strikes the correct balance between benefits and harms, to realise the core goal of 'timely detection' of lethal cancers to improve survival rates.

Throughout the four-day Summer School five delegates trained by Carl Yamashiro (Arizona State University), including Wendy Alderton, Charlie Massie and Daniel Munoz-Espin (CCC Early Detection Programme), Valerie Sills (PHPC, Cambridge), and Cindy Azevedo (Arizona State University), took part in a team activity to work through the stages of developing an early detection test. Working in small groups after each session, delegates covered in greater depth the development process starting from concept and ideation, through considerations for specific technologies, practicalities for implementation, quality systems, assessing competition and IP, regulation, reimbursement, marketing, and final commercialisation. Using a tailored agile development programme, implemented together with the team from Arizona State University, delegates were mentored through the complexities and considerations for realising cancer early detection diagnostics. The team development activity culminated in a series of short presentations at the end of the Summer School and the award of the first International Early Detection Prizes!

Team activity session. Working in small groups, delegates explored the key considerations for the development of cancer early detection tests. Using an agile development process and short 'sprints', facilitated by 'scrum masters' (in this case, Daniel Munoz-Espin).

The feedback for the event was very positive, with 100% of delegates agreeing that the course was well organised and met the key objectives for the topics of Developing Diagnostics for Cancer Early Detection. We had very positive feedback from delegates:

"Amazing range and level of speakers"

"Cytosponge, CancerSEEK, Quake, Immunovia, Cologard were amazing talks. Learned a lot about science, regulatory, clinical validation, societal elements"

"Excellent range of talks, great presenters across the board"

"It was a really good multidisciplinary event and I enjoyed having the opportunity to network with researchers that are tackling the early detection problem form such different viewpoints."

In conclusion, the first International Early Detection Summer School brought together an outstanding team of senior faculty, speakers, associates, and delegates from multiple international institutions sharing the vision of increasing survival from cancer and improving quality of life through early detection and intervention. We are already planning the next International Early Detection Summer School, so watch this space and look out for email alerts to make sure you don't miss out on the next Summer School!
Year(s) Of Engagement Activity 2019
URL https://www.earlydetectioncambridge.org.uk/news-events/news/successful-first-international-summer-sc...
 
Description Interview Life Extension Advocacy Foundation (LEAF) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact During the Fourth Eurosymposium on Healthy Ageing (EHA), which was held in Brussels, Belgium in November 2018, I was interviewed by Life Extension Advocacy Foundation (LEAF), a non-profit organisation dedicated to promoting healthy human lifespan.
Year(s) Of Engagement Activity 2018
URL https://www.leafscience.org/an-interview-with-daniel-munoz-espin/
 
Description Nanoevening Event, Lecture Theatre, Institute for Manufacturing (IfM), West Cambridge, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact This is a "Nanoevening" event organised by the Cambridge University Nanotechnology Society at the Institute for Manufacturing, University of Cambridge, on the 14th of March 2019. This event brings together students and researchers for a cross-disciplinary insight into the Nanotechnology research happening at Cambridge. My talk is aimed at introducing students to novel applications of Nanomedicine, in particular in how to use drug delivery tools to target senescent cells in preclinical models of cancer and disease.
Year(s) Of Engagement Activity 2019
URL https://docs.google.com/forms/d/e/1FAIpQLSe59s-eamJKsSliWlIbHaQUL4ptERSjqKlLzL-hMOqYdaKPpA/viewform
 
Description Organisation of a International Summer School: Discovery and Development of Diagnostics for the Early Detection of Cancer 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact As part of the CRUK Cambridge Centre Early Detection Programme we have organised the first international summer school on discovery and development of diagnostics for the early detection of cancer. As part of the Early Detection Programme Steering Committee I have participated actively in the design and organisation of the summer school. The summer school is aimed at those who are developing new technologies and interventions for the early detection of cancer and those who are interested in exploring this rapidly expanding and exciting field and is open to academic, corporate and student delegates. This ground-breaking summer school will focus on the scientific, clinical and policy challenges of developing and validating new screening technologies and interventions for the early detection of cancer. Participants will hear from experts across multiple disciplines on the science and technology of diagnostics through to clinical trials design, evidence review, regulatory perspectives and pathway to adoption, to the societal impacts of early cancer detection. Companies active in the development early cancer diagnostics, including Exact Sciences and Immunovia, will present case studies on their technologies and give insight into the route to market. In addition, participants will have the opportunity to participate in an opening debate and attend a Gala dinner with the after dinner talk to be given by Billy Boyle of Owlstone Medical Ltd. The summer school will be held in July 2019 in the tranquil surroundings of Robinson College in a state-of-the-art conference facility which is just minutes' walk from the historic city of Cambridge.

The Summer School is aimed at training the next generation of research leaders in discovery and development of novel tools for Early Cancer Detection and Therapy, including product ideation, SWOT analysis, product definition, regulatory/reimbursement, translational steps, clinical trials, marketing, and commercialisation. We will introduce undergraduates, PhD students and postdocs in the industry and partnerships. Over the duration of the school, all delegates will participate in a team activity 'Envisioning New Diagnostics' led by the International School of Biomedical Diagnostics, Arizona State University (ASU), culminating in a presentation on the final day. ASU has considerable experience in this field, already offering a one-year, online Master of Science degree in Biomedical Diagnostics developed together with academic partner Dublin City University (DCU), and industry partners. The degree focuses on the global business and application of diagnostics in the healthcare and research arenas today. Myself and other group leaders have been recently trained in a two days course by Dr Carl Yamashiro (ASU) to lead the team activity as "Scrum Masters". Of note, David Macias-Gutierrez, senior postdoc in my lab and associated with this award, has also been trained as "Scrum Master".
Year(s) Of Engagement Activity 2019
URL https://www.earlydetectioncambridge.org.uk/news-events/international-summer-school
 
Description Participation in the Cambridge Science Festival - Cambridge Academy for Science and Technology 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact My laboratory has been invited to contribute an activity in the Cambridge Science Festival 2019, as part of the CRUK Cambridge Centre Early Detection Programme. We have prepared different activities in a stand with a background of Cancer Early Detection. This includes a human torso model, a lung model, a real lung, an early detection activity to detect tumours with a UV fluorescent light in a lung model, a pinball game containing targetable tumours, and and adaptation of the "Invaders" computer game of the 80´s to a game with tumour cells (instead of invaders) and a therapeutic syringe shooting nanoparticles (instead of a spacecraft).
Year(s) Of Engagement Activity 2019
URL https://www.sciencefestival.cam.ac.uk/browse-2019-programme
 
Description Preparation of a Video presenting the mission of the CRUK Cambridge Cancer Centre Early Detection Programme 
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 As part of the CRUK Cambridge Cancer Centre Early Detection Programme I am involved in the generation of a video summarising the goals and mission of the Programme. I have been involved in the writing of the script and the design of the animations. This video will be included in the website of the Early Detection Programme and in Events for the general public.
Year(s) Of Engagement Activity 2019
URL https://www.earlydetectioncambridge.org.uk
 
Description Video presenting the mission and scope of the CRUK Cambridge Centre Early Detection Programme 
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 As group leader of the CRUK Cambridge Centre Early Detection Programme I generated a video summarising the goals and mission of the Programme. I have been involved in the writing of the script and the design of the animations. This video is included in the website of the Early Detection Programme and used in relevant Events for the general public.
Year(s) Of Engagement Activity 2019
URL https://www.earlydetectioncambridge.org.uk