Molecular origins of metastatic cancer phenotypes

Lead Research Organisation: University of Cambridge

Abstract

The spread of cancer to distant organs in a process termed metastasis is one of the most devastating aspects of cancer, being the cause of ~90% of cancer-related deaths. The vast majority of metastatic cancers are refractory to treatment and are therefore incurable. Thus, there is a pressing clinical need for further research on the molecular basis of metastatic cancer. Our approach combines state-of-the-art experimental cancer models, functional genetics and computer-based analysis of cancer data sets to identify genetic factors that are required for the growth and maintenance of metastatic cancer. The expected benefit from this work is a better understanding of the molecular mechanism that drive cancer metastasis. This knowledge will serve as a basis for the development of rational therapeutic strategies to combat metastatic cancer. Thus, the potential secondary benefits of this work will go beyond basic cancer research, possibly leading to the identification of (i) new molecular targets for metastatic cancer and (ii) novel predictive and/or prognostic biomarkers for metastatic cancer.

Technical Summary

Metastatic dissemination remains one of the most devastating complications of cancer. In the clinic, metastases often present as the final step of disease progression, but the molecular origins of metastases may be rooted in the early steps of carcinogenesis. Several lines of evidence suggest that instead of specific mutations, metastatic phenotypes can emerge from optimized output of the oncogenic pathways that drive tumour initiation and early progression. The molecular mechanisms as well as phenotypic consequences of such optimization of pathway output remain elusive. Yet, understanding how metastatic cancer phenotypes arise and persist, to what extent this is dependent on the pathways that drive tumour initiation and early progression, and what genetic vulnerabilities advanced cancer clones have could profoundly affect our ability to fight metastatic cancer.
Using an integrative approach combining experimental cancer models, high-throughput genomics, functional genetics, bioinformatics and clinical association analysis, this programme aims at identifying genetic dependencies in metastatic cancer. With a focus on VHL mutant renal cancer, we will explore molecular mechanisms that modulate the phenotypic output of tumour-initiating mutations in support of metastasis, and test the hypothesis that this optimisation of oncogenic signalling results in molecular vulnerabilities in the most aggressive cancer clones. Understanding the origins of metastatic cancer phenotypes will provide insights into the fundamental requirements of cancer cell states and help identify functionally relevant biomarkers as well as therapeutic targets. Knowledge of the molecular networks that bolster the output of tumour-initiating genetic pathways in cancer progression may also have implications for early intervention strategies for cancer.
 
Description Modelling therapeutic susceptibilities of the von Hippel-Lindau disease-associated kidney lesions in genetically engineered mice
Amount £199,366 (GBP)
Funding ID RP_033_20170303 
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 03/2021
 
Description PhD Scholarship
Amount £27,000 (GBP)
Organisation Majlis Amanah Rakyat (MARA) 
Sector Public
Country Malaysia
Start 01/2015 
End 12/2017
 
Description PhD Scholarship
Amount £27,000 (GBP)
Organisation The National University of Malaysia (MUM) 
Sector Academic/University
Country Malaysia
Start 01/2015 
End 12/2017
 
Description Frontiers in Metastasis Biology - Advanced workshop 
Organisation Research Institute of Molecular Pathology (IMP)
Country Austria 
Sector Academic/University 
PI Contribution Advanced training of the next generation of experts in metastasis research.
Collaborator Contribution A three-day intensive and interactive course on metastasis biology aimed at PhD students and early-career postdocs. Organised in rotation as a tri-institutional collaboration between University of Cambridge, University of Basel and Research Institute of Molecular Pathology, Vienna.
Impact Training of young scientists in advanced metastasis biology. First event held in Basel 2018, the second even in Cambridge 2019.
Start Year 2018
 
Description Frontiers in Metastasis Biology - Advanced workshop 
Organisation University of Basel
Country Switzerland 
Sector Academic/University 
PI Contribution Advanced training of the next generation of experts in metastasis research.
Collaborator Contribution A three-day intensive and interactive course on metastasis biology aimed at PhD students and early-career postdocs. Organised in rotation as a tri-institutional collaboration between University of Cambridge, University of Basel and Research Institute of Molecular Pathology, Vienna.
Impact Training of young scientists in advanced metastasis biology. First event held in Basel 2018, the second even in Cambridge 2019.
Start Year 2018
 
Description Scientific collaboration with IMP Vienna 
Organisation Research Institute of Molecular Pathology (IMP)
Country Austria 
Sector Academic/University 
PI Contribution We have collaborated with Anna Obenauf's group at IMP on a scientific project that has resulted in new understanding of how immunotherapy works in cancer.
Collaborator Contribution The Obenauf lab has generated a lot of experimental data on how immunotherapy works in cancer.
Impact Bioinformatics, medicine, experimental cancer biology.
Start Year 2019
 
Description Scientific collaboration with Tsinghua University 
Organisation Tsinghua University China
Country China 
Sector Academic/University 
PI Contribution We have collaborated with the Charles David lab at the Tsinghua University by helping them generate a tandem sgRNA library that can be used to screen for enhancer activity in experimental systems.
Collaborator Contribution Dr David's lab has generated a lot of experimental data to understand the role of Kras in pancreatic carcinogenesis. The tools we have generated for the project support further analysis of their model.
Impact Generation of novel experimental tools.
Start Year 2019
 
Description "Arts Meet Science" public lecture. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Dr Sakari Vanharanta spoke at an event to celebrate confluence across various disciplines and cultures.
The public event themed "Arts Meet Science" held at the Beaconsfield Gallery, Vauxhall, London was organised by the Finnish Institute.
Year(s) Of Engagement Activity 2018
 
Description 2) Participation in Cambridge University Science Festival (2015, 2016, 2017, 2018) 
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 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 Vanharanta 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 Guest at the Finding Genius podcast 
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 Guest at the Finding Genius podcast
Year(s) Of Engagement Activity 2020
URL https://www.findinggeniuspodcast.com/podcasts/mapping-metastasis-with-sakari-vanharanta-md-phd/
 
Description Guest at the Naked Scientist radio 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 Guest at the Naked Scientists programme, aired live on BBC Radio Cambridgeshire, and broadcast on BBC 5 Live and ABC's Radio National Australia. Also available online as a longer podcast version.
Year(s) Of Engagement Activity 2020
URL https://www.thenakedscientists.com/articles/interviews/cancer-metastasis-why-does-cancer-spread
 
Description Interview for national news 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interview and coverage of our work in New Scientist (7 June 2018).
Year(s) Of Engagement Activity 2018
URL https://www.newscientist.com/article/2171001-kidney-cancer-spreads-by-pretending-to-be-white-blood-c...
 
Description NCRI Cancer Conference Career Session 2019 
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 About 20 participants attended a career advice session at the NCRI Cancer Conference 2019.
Year(s) Of Engagement Activity 2019
URL https://conference.ncri.org.uk/2019-programme/
 
Description National news 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Coverage of our work in the news paper Daily Mail (24 July 2018).
Year(s) Of Engagement Activity 2018
 
Description Participation in MRC Festival of Science Open Day 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.The event was also replicated in 2017 with 4 schools (but with more number of students from each school, due to popular demands) visiting the MRC Cancer Unit on 20th June 2017. 60 students were given a similar tour as above .
Year(s) Of Engagement Activity 2016,2017,2018
URL https://mrccancerunit.wordpress.com/2016/07/06/inspiring-the-next-generation-of-cancer-researchers-t...