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 Cancer Grand Challenges 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 Cancer Grand Challenges 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 Cancer Grand Challenges 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”.