Established in 2015 by Cancer Research UK, the initiative will provide five grants of up to £20 million each to research teams working on one of seven Challenges. The seven Grand Challenges, chosen for their potential to transform progress against cancer, were selected by a panel of influential scientists, working with cancer researchers and patients worldwide (see The Grand Challenge: tackling the toughest cancer questions for details of the Challenges).

Cancer Research UK then invited the research community to form multidisciplinary teams and submit proposals to answer the Challenges. High-quality applications were submitted by more than 200 institutes from 25 countries, uniting more than 400 research groups. Nine teams were shortlisted last year and today, four winners were picked.

"Cancer Research UK set up the Grand Challenge awards to bring a renewed focus and energy to the fight against cancer," explained Cancer Research UK's chief executive Harpal Kumar. "We want to shine a light on the toughest questions that stand in the way of progress. We're incredibly excited to be able to support these exceptional teams as they help us achieve our ambition."

Originally, the Grand Challenge planned to fund one new team every year for five years. However, the exceptional quality of the submissions led to the selection panel deeming several proposals too important not to fund. Extra funding from a partnership with the Dutch Cancer Society and an anonymous donor has enabled four proposals to be funded, with the first round of Grand Challenge funding now totalling up to £71m.

The four winning project are listed below:

• Understanding the causes of cancer
This project will study thousands of cancer samples to better understand the DNA damage associated with different cancers. Addressing Grand Challenge 3 - "to discover how unusual mutation patterns are induced by different cancer-causing events" - the project will be led by Mike Stratton at the Wellcome Trust Sanger Institute, with collaborators from France, the USA and the UK.

Environmental factors and behaviours such as smoking and drinking alcohol can cause cancer by damaging cells' DNA, leaving a distinctive pattern known as a mutational fingerprint. While scientists know of around 50 cancer-associated mutational fingerprints, they only know what causes about half of them. Stratton and co-workers aim to link these mutational signatures back to the events that caused them.

By examining mutational fingerprints in 5000 samples collected from cancer patients across five continents, the team hopes to identify as yet unknown causes of cancer, determine which ones are due to environmental exposures and lifestyle behaviours, and figure out exactly how they cause cancer. This research could dramatically improve understanding of what causes cancer, lead to better information on how to reduce cancer risk, and help inform government policies to reduce exposure to cancer-causing agents.

• When is cancer not really cancer?
Addressing Grand Challenge 4 - "to distinguish between lethal and non-lethal cancers" - this study is designed to differentiate women with ductal carcinoma in situ (DCIS) who need treatment from those who don't. This project will be led by Jelle Wesseling at the Netherlands Cancer Institute with collaborators from the USA, UK and Netherlands.

DCIS is a condition that can sometimes develop into breast cancer. Currently, however, doctors can't tell whether a patient's DCIS is harmless or hazardous, resulting in many patients undergoing unnecessary treatment. The team hope to change this, by studying tissue samples taken from women with DCIS during surgery. They will examine the genetic make-up of these samples, and determine which immune cells they contain. Alongside, they will gather clinical information about the patients, recording whether their DCIS came back, whether they later developed breast cancer, and if so, whether it spread.

The researchers will then combine these data and use mathematical modelling to search for biomarkers in the DNA that can distinguish between DCIS patients with a low and high risk of developing cancer. Potential biomarkers will then be tested in larger clinical trials for women with DCIS.

• Charting unknown territory
This project aims to combine new and existing technologies to develop a reproducible, standardized way to map tumours in unprecedented detail. Tackling Grand Challenge 5 - "to map tumours at molecular and cellular levels" - the research will be led by Josephine Bunch at the National Physical Laboratory, with collaborators from the USA and multiple UK research centres.

The researchers will use a variety of new mass spectrometry imaging techniques and instruments that they have developed to study individual breast, bowel and pancreatic tumours in exceptional detail. They plan to map and visualize every part, from the whole tumour down to individual fats and proteins in cells, as well as the tumour microenvironment, to create detailed 3D representations of these tumours.

The team will also generate a database containing their data that will be available to researchers around the globe, and work to create a standardized way for other scientists and doctors to use these techniques to study other cancers. This novel approach to studying and mapping the entire molecular make-up of tumours could help identify new and better ways to diagnose and treat cancer.

• Building a virtual reality map of breast cancer
Also addressing Grand Challenge 5, this project team aims to build a 3D tumour that can be studied using virtual reality and which shows every different type of cell in the tumour. The project will be led by Greg Hannon at the University of Cambridge, with collaborators from Switzerland, Ireland, Canada, the USA and the UK.

Combining established techniques, such as DNA sequencing and imaging, with new technology that they will develop, the team will study breast cancer samples collected from women involved in the METABRIC study. They plan to gather thousands of bits of information about every cell in a tumour - from cancer cells to immune cells - to find out what cells are next to each other, how they interact with and influence each other, and how they work together to help tumours survive and grow.

The researchers will then use this information to construct a 3D version that can be studied using virtual reality. This will allow scientists and doctors to examine, for the first time and in unprecedented detail, the cellular and molecular make-up of a patient's entire tumour. By developing such an entirely new way to study cancer, this team hopes to change how the disease is diagnosed, treated and managed.

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