Manipulating the microbiome to beat bowel cancer

 

A team of 14 investigators led by Professors Matthew Meyerson and Wendy Garrett

Canada, The Netherlands, Spain, USA and UK 

Genomicists, microbiologists, geneticists, immunologists, biologist, epidemiologists and pathologists

 5 years

 

Background

The human body is home to trillions of different microorganisms including bacteria, fungi and viruses. Together, they form a community called the microbiota, which differs from organ to organ and person to person.

Scientists have shown that these microorganisms have important roles in maintaining human health, but they can also play a role in the development of disease – including cancer.  More recently, it has become apparent that the microbiota can affect how cancer patients respond to certain treatments. Understanding these microorganisms stacks up to a monumental global challenge.

Professors Matthew Meyerson and Wendy Garrett are leading an international collaboration, spanning five countries, to discover exactly how certain microbes inside the body lead to cancer development and influence a patient’s response to treatment. 

The research

Professors Meyerson and Garrett's team brings together experts from the USA, UK, Canada, The Netherlands and Spain. Gaining a true and comprehensive understanding of anything requires analysing a problem from multiple angles – fortunately, the specialists put together to work on this project have that covered. Using their complementary skillsets, they will analyse the microbiota on diverse fronts using their expertise in cancer biology, clinical trials, cancer modelling and immunology.

Firstly, they’ll undertake exploration and prototyping. Powerful imaging techniques will allow the team to visualise the complex interactions between bacteria, cancer cells, immune cells, and healthy cells. This knowledge will be invaluable for building test models of the cancer-microbiota interactions to spot weaknesses and test treatments.

Secondly, in a truly collaborative effort, they’ll gather intelligence. Using samples from existing bowel cancer population studies that span decades, the team aim to find links between the microbiota, tumour and patient characteristics. These studies represent an unparalleled resource, and delving deep into the data could unveil new ways of preventing the disease.

Whilst the above work is ongoing, the team will capture the outputs and use them for two fresh strategies to tackle bowel cancer.
1. They’ll explore a variety of ways to modulate the microbiome in model systems of cancer, to prevent certain bacterial species from driving cancer growth, and where feasible, will test these approaches in patients.
2. The team will look to understand how bacteria can influence a cancer patient’s response to existing drugs, exploiting any areas of weakness.

The impact 

The scope of Professors Meyerson and Garrett's ambitious plan is unprecedented. By the end of the project, they aim to have revolutionised understanding of the role the microbiota plays in cancer development, found new ways of preventing bowel cancer, and defined new treatment strategies through manipulating the gut microbiota. By taking on a challenge of such epic proportions, the team hope to galvanise the entire research community working in this field, starting an expansion of innovative approaches to tackling bowel cancer.

Background

Our intestines are colonised by trillions of microorganisms, largely bacteria. For the most part, the relationship is mutually beneficial – in return for a protected, nutrient-rich environment, gut bacteria assist with digestion and afford protection from pathogenic microorganisms.

To live in harmony with this vast microbial metropolis, the immune system constantly calibrates itself to ensure that commensal bacteria are tolerated but that immune surveillance against more harmful species is maintained.

It’s this delicate balance that maintains gut health, and perturbations which upset this balance have been implicated in the development of several diseases of the colon, including colorectal cancer.

In recent years, the research landscape has been ablaze with reports linking different bacterial species to colorectal cancer incidence, response to therapy and even treatment side-effects. But few studies have grappled with these issues at scale, and none have offered a comprehensive account of how the specific composition of the microbiome affects disease trajectory.

Introducing OPTIMISTICC

Enter OPTIMISTICC (Opportunity To Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer) – an international team led by Matthew Meyerson, MD, PhD, and Wendy Garrett, MD, PhD. Their goal is to pinpoint the mechanisms by which the microbiome impacts the initiation and progression of colorectal cancer and to apply this understanding for therapeutic benefit.

The team comprises geneticists, immunologists, oncologists, microbiologists and patient advocates, each of whom are pioneers in their respective fields.

In an ambitious plan that spans the translational pipeline, the aim is to integrate these diverse yet complementary perspectives to provide a 360° view of the role of the microbiota in colorectal cancer.

Understanding how microbial species and patterns alter disease risk

Size matters when it comes to epidemiological studies; it’s the bottleneck that has limited many previous studies of how the gut microbiome affects colorectal cancer risk.

But the sheer scale of Grand Challenge has allowed the team to overcome this barrier and analyse samples from over 17,000 people at risk of familial or sporadic forms of colorectal cancer by 16S rRNA amplicon sequencing, qPCR, together with metagenomics and metabolomics assays.

And in an exciting collaboration between two Grand Challenge teams, the OPTIMISTICC team will retrieve previously discarded bacterial sequences from global datasets afforded through the Mutographs project.

The power of this unique dataset comes from its accompanying epidemiological data, which will allow the group to correlate specific bacterial species with lifestyle factors and geographical location.

Integrating these data will provide – for the first time – a clear picture of the complex interplay between the microbiota and other factors in determining disease risk. Together, the team hope that their findings will drive novel strategies to prevent colorectal cancer.

Defining the interaction between microbe and host cells

The project will also map and model interactions between the microbiota and host cells within colorectal tumours using imaging techniques, murine models and organoid culture systems. These experiments will address crucial questions pertaining to the specific cell types targeted by the microbiota, whether the bacteria exert their effects inside or on the surface of target cells, and the cellular signalling pathways perturbed by the interactions.

The team will also interrogate the hypothesis that mechanisms employed by the microbiome to down-regulate local immunity in the gut might explain why immunotherapies have thus far been disappointing against most types of colorectal cancer.

Reconstituting these interactions in preclinical models will facilitate the identification of the key molecular moieties involved – potentially generating new strategies to boost the potency of immunotherapies.

Cross-talk between the microbiome and treatment

Moving further towards the clinic, the team will explore how the microbiome modulates – and is itself modulated by – treatment. At the heart of the investigation is a prospective sample collection of blood, tumour tissue and stool taken from colorectal cancer patients from all over the world.

Samples will be interrogated using a variety of techniques including whole-genome sequencing, single-cell transcriptomic analysis, metabolomic analysis and histopathology.

This information will be layered with detailed clinical and lifestyle data, to develop a one-of-a-kind resource which will serve as a springboard for subsequent studies into the role of the microbiome and colorectal cancer for years to come.

The microbiome as a therapeutic treasure trove

The team's final challenge is to explore the idea of using the microbiome as a source of therapeutics. A clinical trial will determine whether the addition of a defined microbial cocktail is safe and well-tolerated in patients and address questions of whether such cocktails can keep oncomicrobial species at bay. And large-scale compounds screens will run in parallel to identify novel compounds that significant impair the growth of oncomicrobial species.

The group will also test a vaccine-based approach – harnessing bacterially-derived epitopes to elicit innate T-cell responses.

Finally, they’ll also investigate a curious class of microbes collectively known as predatory bacteria. While these species pose no risk to human health, they seek out and target other bacteria, and their prey preference can be manipulated. So OPTIMISTICC will elucidate whether these micro-organisms might represent an intriguing new addition to our arsenal of cancer treatments.

The bigger picture

While their project is focussed on colorectal cancer, Garrett and Meyerson are confident that their findings will help set the direction of travel of many future studies of the role of the microbiome in other cancers.

To catalyse this movement, they’re keen to ensure that the datasets and resources generated by their project are shared with the wider community, and that their findings are disseminated with minimal delay.

Both are convinced that Grand Challenge has given them a once-in-a-lifetime opportunity to collaborate with the world’s brightest minds to perform transformative science on an unparalleled scale. And they’re particularly excited about the possibility of having a genuine impact on patient survival. As Meyerson asserts: “I think we’re going to have a lot of surprises”.

 

Terry Kavanagh ​

Grand Challenge patient panel

"As a patient, I want to hurry this project on, like skipping pages in a book to find out what happens in the end. I am in awe of the scientists and their daring to delve into a project as complex as trying to unravel the secrets of the microbiota. This is an appealing research project which everyone -patient or not - can benefit from."

Prof. Suzanne Cory introduces Prof. Meyerson and Garrett's Grand Challenge

 

The role of the cancer microbiota remains one of the big mysteries in cancer biology. We are excited that our proposal will be supported by Cancer Research UK's Grand Challenge as it will enable our team to transform understanding of how the colon cancer microbiome influences cancer growth, diagnosis and response to treatment.

Professor Matthew Meyerson, Joint Principal Investigator

The team

 

Professor Wendy Garrett

Principal Investigator
Professor of Immunology and Infectious Diseases

Country: USA
Organisation: Harvard T.H. Chan School of Public Health 
Discipline: Immunology & infectious diseases

 

Professor Matthew Meyerson

Principal Investigator
Professor of Pathology and Director of the Center for Cancer Genome Discovery

Country: USA
Organisation: Dana-Farber Cancer Institute, Harvard Medical School
Discipline: Cancer genomics

 

Professor Emma Allen-Vercoe

Professor of Molecular and Cellular Biology

Country: Canada
Organisation: University of Guelph
Discipline: Microbiology

 

Professor Hans Clevers

Professor of Molecular Genetics 

Country: The Netherlands
Organisation: Hubrecht Institute
Discipline: Molecular genetics

 

Dr Marios Giannakis

Instructor in Medicine

Country: USA
Organisation: Dana-Farber Cancer Institute, Harvard Medical School
Discipline: Gastrointestinal oncology

 

Professor Robert Holt

Professor of Molecular Biology & Biochemistry and Head of Sequencing

Country: Canada
Organisation: BC Cancer Agency​
Discipline: Medical genetics

 

Dr Curtis Huttenhower

Associate Professor of Microbial Metagenomics

Country: USA
Organisation: Harvard T.H. Chan School of Public Health​
Discipline: Microbial metagenomics

 

Professor Kimmie Ng

Assistant Professor in Medicine

Country: USA
Organisation: Dana-Farber Cancer Institute, Harvard Medical School
Discipline: Gastrointestinal oncology 

 

Professor Shuji Ogino

Professor of Pathology and Epidemiology

Country: USA
Organisation: Dana-Farber Cancer Institute, Harvard Medical School
Discipline: Molecular pathological epidemiology

 

Professor Fiona Powrie

Professor of Microbiology & Immunology 

Country: UK
Organisation: University of Oxford​
Discipline: Microbiology & immunology

 

Professor Philip Quirke

Professor of Pathology

Country: UK
Organisation: University of Leeds
Discipline: Pathology

 

Professor Cynthia Sears

Professor of Medicine

Country: USA
Organisation: Johns Hopkins University School of Medicine
Discipline: Medicine, infectious diseases

 

Dr Josep Tabernero

Director of the Vall d’Hebron Institute of Oncology

Country: Spain
Organisation: Vall d’Hebron Institute of Oncology
Discipline: Medical oncology

Dr Laura Porter

Patient Advocate

Country: USA
Organisation: Independent medical advisor and patient advocate​
Discipline: Medicine, advocacy

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