PROMINENT
Normal Phenotypes: Understand how cells and tissues maintain "normal" phenotypes whilst harbouring oncogenic mutations and how they transition to become a tumour.


Professor Allan Balmain, Co-Team Lead
Barbara Bass Bakar Distinguished Professor of Cancer Genetics
PROMINENT

Dr Paul Brennan, Co-Team Lead
Branch Head, Genomic Epidemiology
PROMINENT

Professor Nuria Lopez-Bigas, Co-Team Lead
ICREA Research Professor
PROMINENT
INSTITUTIONS
6
LOCATIONS
UK, US, France, Spain
FUNDED BY
Cancer Research UK, National Cancer Institute, Asociación Española Contra el Cáncer
SPECIALISMS
Epidemiology, genomics, animal modelling, machine learning, community engagement and cancer prevention
Stopping cancer before it starts
Funded by:

The PROMINENT team will investigate the promoter hypothesis – an alternative theory about the very early stages of cancer development – seeking to answer important questions about tumorigenesis and find new ways to prevent the disease.
Although the accumulation of mutations in cells has long been assumed to trigger tumorigenesis, recent studies suggest a much more complex relationship: cells often carry many known cancer-causing mutations yet remain phenotypically normal. These cells, despite their remarkable genetic similarities with cancer cells, do not form tumours.
Does an intrinsic mechanism within the cell or its environment protect against tumorigenesis? How do processes such as inflammation, ageing or exposure to certain carcinogens influence the behaviour of cells already carrying cancer-causing mutations? Through the Normal Phenotypes challenge, the PROMINENT team will consider deep biological questions regarding what makes cells ‘normal’, the protective mechanisms that keep them that way and the steps that trigger early tumour development.
The team will investigate an alternative model of carcinogenesis, the promoter hypothesis, in which cells exposed to mutagenic carcinogens accumulate cancer-driving mutations but remain dormant. After exposure to a ‘promoting’ stimulus, such as chronic wounding, these ‘initiated’ cells, through an unknown mechanism, gain a selective advantage allowing them to undergo clonal expansion and progress to malignancy.
With a deeper understanding of the very early stages of cancer development, the team plans to build a ‘roadmap’ as a cell travels down the pathway to malignancy, looking for opportunities to target the critical moment of transition and find new routes to prevention and treatment.
Addressing the Normal Phenotypes challenge
The team will be using a unique collection of resources, including a tissue bank of more than 4,000 mouse samples across all stages of carcinogenesis, and an extensively annotated collection of pairs of tumour and healthy tissue samples provided by more than 5,000 people across 20 countries, collected by the team taking on our Unusual Mutation Patterns challenge. Serial biopsies of normal tissues will also be collected from people participating in intervention studies focused on obesity and smoking. A range of genomic and screening techniques will be used, including human organoid culture and CRISPR-Cas9 gene editing. All data will be collected in a central repository and analysed with molecular-evolution and machine-learning models to identify the molecular signatures and mechanisms of cancer promotion.
The team hopes to answer four major questions:
- What are the environmental, lifestyle or endogenous risk factors that promote the selection of pre-initiated cells in normal tissue?
- Which cells carry initiating mutations, where are they located, how are they selected for during ageing, and what is their relationship with normal and cancer stem cells?
- Which mechanisms promote the first signs of neoplastic growth, and what additional changes cause transition to full malignancy?
- How can we intervene to prevent the earliest stages of neoplastic cell selection by tumour promoters?
Answering these questions and understanding the mechanisms causing initiated cells to transition to cancer cells could offer new possibilities for intervention and cancer prevention. In particular, the team hopes to investigate a novel group of compounds, which they refer to as ‘promolytics’, which may be able to prevent or reverse the promotion step.
By uniting across boundaries, the PROMINENT team hopes to bring a new perspective to fundamental questions surrounding early tumour development and identify novel routes to prevention.

Professor Allan Balmain, Co-Team Lead
Barbara Bass Bakar Distinguished Professor of Cancer Genetics
As a research community, we’re on the verge of a major leap forward in our understanding of the factors that contribute to the risk of cancer, which could help to find new, informed ways to stop cancer before it even starts.
Allan Balmain was born in Wick, Scotland, studied Organic Chemistry at the University of Glasgow, and carried out post-doctoral work France and Germany. He subsequently worked in the University of Glasgow and Beatson Institute for Cancer Research, before moving to the United States in 1997.
Allan established a molecular link between chemical carcinogen exposure and initiation of tumour development in 1983, and showed that the types of mutations found in oncogenes depend on the causative chemical agent. A major focus has been the links between genetic and environmental factors and how they interact to cause cancer susceptibility. Allan is also a co-investigator on the Cancer Grand Challenges Mutographs team, taking on the Unusual Mutation Patterns challenge.
Organisation
University of California, San Francisco

Paul Brennan runs the Genetics Section at the International Agency for Research on Cancer (IARC) in Lyon. The primary aim of the Genetics Section is to use genetics and genomics techniques to (i) understand the causes of cancer, and (ii) identify ways to detect and treat cancers at earlier stages.
In the Mutograph Grand Challenge he will coordinate the large international effort of recruiting approximately 5000 cancers across 5 continents for 5 different cancers types.
Organisation
International Agency for Research on Cancer
Discipline
Epidemiology

Nuria Lopez-Bigas is a biologist with a PhD in molecular genetics of deafness. She transitioned into bioinformatics during her postdoc at the European Bioinformatics Institute (EBI). Since 2006, she leads a research group in Barcelona focused on the study of cancer from a genomics perspective. She is particularly interested in the identification of cancer driver mutations, genes and pathways across tumor types and in the study of their targeted opportunities.
She is also interest in understanding the mutational processes leading to the accumulation of mutations in cancer cells. Her lab has done important contributions in the discovery of the variation of mutation rate along the genome. They have recently discovered that transcription factors (TF) and nucleosomes interfere with DNA damage and DNA repair producing variable mutation rate along TF binding sites and nucleosomes covered regions.
Organisation
Institute for Research in Biomedicine

Professor Kim Rhoads, a board-certified general and colorectal surgeon, with additional training in basic cancer research, epidemiology, health services research, health policy and community-based participator research. Kim currently serves as the inaugural Associate Director for Community Engagement at the UC San Francisco Helen Diller Family Comprehensive Cancer Center. Kim is an innovator in disparities research and a national leader in community and stakeholder engagement. She was the first to highlight the correlation between care utilization patterns, quality of care and disparities in cancer survival. She was also the first investigator to validate National Comprehensive Cancer Network guideline base care at a population.
Organisation
University of California, San Francisco

Luke Gilbert is an Assistant Professor in the Department of Urology, the Department of Cellular and Molecular Pharmacology, the Helen Diller Family Comprehensive Cancer Center and an Investigator in the Innovative Genomics Institute at the University of California, San Francisco. Luke was an early pioneer in repurposed CRISPR systems that are used to turn genes on (CRISPRa) and off (CRISPRi) by editing the epigenome. More recently, the Gilbert lab has developed new strategies for editing heritable epigenetic memories (CRISPRoff/on) and for systematically mapping human genetic interactions at very large scales or at single cell resolution. The Gilbert lab is focused on using CRISPR to tackle big problems in human biology with a special focus on cancer.
Organisation
University of California, San Francisco

Dr. Calvin Kuo MD, PhD is the Maureen Lyles D’Ambrogio Professor of Medicine at Stanford University School of Medicine. His research interests include modeling of cancer, immunity and pathogens in 3D organoid cultures, biology of intestinal and lung stem cell populations, and molecular regulation of angiogenesis and the blood-brain barrier. He is an elected member of the Association of American Physicians, American Society for Clinical Investigation and AAAS, has founded several biotechnology companies and serves on numerous foundation boards.
Organisation
Stanford University

Christopher M. Counter, Ph.D. is the George Barth Geller Distinguished Professor of Pharmacology at Duke University, as well as the Associate Director of Basic Research for the Duke Cancer Institute. Dr. Counter has a long history of defining the events that convert a normal cell into a tumor, beginning with identifying one of the original hallmarks of cancer, immortalization through activation of telomerase, as a steppingstone to recreate tumors from normal cells using defined genetic alterations. This work led to a focus on the earliest events, namely how initiation mutations in RAS genes begin the process of tumorigenesis. Dr. Counter thus brings a wealth of experience in culture and mouse models of early tumorigenesis as well as technologies for capturing and manipulating these events in an effort to understand how cells with initiating mutations are promoted towards more tumorigenic fates.
Organisation
Duke University

Dr Gunter is Professor and Chair in Cancer Epidemiology and Prevention in the Department of Epidemiology and Biostatistics at the School of Public Health, Imperial College London and co-directs the Cancer Epidemiology and Prevention Research Unit based at Imperial College and the Institute of Cancer Research. He holds a Ph.D in molecular Epidemiology from Cambridge University and a degree in biochemistry from University of Oxford. He completed his post-doctoral training at the U.S National Cancer Institute and has held faculty positions at Albert Einstein College of Medicine in New York and Imperial College London. He previously headed the Nutrition and Metabolism Branch at the International Agency for Research on Cancer (IARC).
He is a molecular epidemiologist and his main research focus is the role of nutrition, diabetes, and obesity in cancer development and prognosis, with an emphasis on studying the mechanisms linking metabolic dysfunction and endocrine pathways with cancer. Marc serves as joint coordinator of the European Prospective Investigation into Cancer (EPIC), a Cohort of more than 520,000 Europeans, and currently leads a number of large-scale multi-disciplinary projects focused on cancer etiology and prevention that employ molecular approaches within prospective cohorts and intervention studies. He has published more than 550 scientific articles and book chapters and serves on numerous scientific committees and panels for international organisations focused on causes of cancer and prevention.
Organisation
Imperial College London

Dr Emma Lundberg is Associate Professor of Bioengineering and Pathology at Stanford University, and Director of the Cell Atlas, of the Human Protein Atlas program. In the interface between bioimaging, proteomics and artificial intelligence her research aims to define the spatiotemporal subcellular architecture of the human proteome, to understand how variations in protein expression patterns contribute to cellular function and disease. Emma has a keen interest in citizen science using computer games, and has engaged over 300,000 gamers to help her classify images in the first ever MMO citizen science computer game.
Organisation
Stanford Medicine

Organisation
Eastern Cooperative Oncology Group-American College of Radiology Imaging Network

Organisation
Cancer Patients Alliance, Pacific Grove, California
