A new way to tackle inflammation-associated cancer

 

A team of 14 led by Professor Thea Tlsty

Canada, Israel, UK and USA

 Biologists, bioengineers, immunologists, gastroenterologists and pathologists

 5 Years

 

Background

Inflammation is the body’s first line of defence – cells of the immune system are recruited to fight dangers, such as infection, and to restore injured tissues back to their original healthy state. This is normally a very tightly controlled process. But sometimes it can spiral out of control and become chronic, aiding the formation of cancer. Globally, an astounding 20-25% of cancers are linked to chronic inflammation, including cancers of the oesophagus (foodpipe), bowel and pancreas.

Professor Thea Tlsty’s team is determined to tackle this problem. Leading a diverse team of experts that spans three continents, they want to find out whether it’s possible to treat the inflamed cells and tissues surrounding a tumour, rather than directing therapies at the tumour itself. This Grand Challenge project aims to find novel ways of treating cancer that has been caused by inflammation, and develop new options to prevent cancer developing in high-risk patients with chronic inflammatory diseases.

The research

When treating cancer, aiming to kill a tumour directly can kick-start tumour cells into ‘survival mode’ – leading to treatment resistance or the spread of cancer around the body. Professor Tlsty’s team, composed of experts in biology, physics and engineering from the USA, Israel, Canada and the UK, plans to take a different approach – by working with the neighbourhood of cells and tissues surrounding the tumour.

The team plans to utilise the type of cells that naturally thrive in and around a tumour, and engineer these cells to release therapeutic agents. But rather than targeting the tumour itself, these therapies will be directed at the tumour’s neighbouring cells and tissues – restoring chronically inflamed tissues to a healthy state. The team wants to find out whether this approach will gradually guide tumour cells back to a non-cancerous, benign state, or help prevent the tumour from growing further. If so, the tumour cells will be less likely to initiate survival mechanisms that can hinder therapy – and therefore respond well to treatment aiming to shrink the tumour in the future.

The impact 

This international team will combine their multidisciplinary expertise with cutting-edge research and technologies, challenging the way we currently treat cancer that is caused by inflammation. The research could also dramatically influence our ability to prevent this type of cancer in high-risk patients. Ultimately, their novel approach to preventing and treating inflammation-associated cancer could benefit up to 1 in 4 cancer patients around the globe.

Background

The human immune system is one of nature’s most sophisticated defence systems. One of the most powerful tools in its armoury is inflammation – a carefully choreographed manoeuvre designed to eject, expel and eliminate pathogens, diseased cells or toxins.

In health, the inflammatory response is an acute one, which is crucial to avoid sustained collateral damage to surrounding tissues. But occasionally, the molecular checkpoints that quench the process fail to engage and the inflammation fails to resolve, leaving the tissue unable to restore its normal structure and function.

This smouldering, chronic inflammation is a significant risk factor for many different types of cancer, including many of the most aggressive and lethal forms of the disease, but the molecular mechanisms underpinning this association remain largely unknown.

That’s exactly what Thea Tlsty’s Grand Challenge team wants to change. Their project – known as STORMing (STrOmal ReprograMing) Cancer – is designed to understand how inflammation propels tumorigenesis, and to define how stromal cells and the extracellular matrix (ECM) contribute to the process.

A new take on tumorigenesis

The integrity of epithelial cells is maintained by a constant stream of cross-talk between the epithelial and mesenchymal layers. Their guiding hypothesis is that chronic inflammation erodes these interactions through structural alterations to the ECM and the provision of pro-inflammatory cytokines by stromal cells. Together, these alterations drive cell plasticity, promoting a more undifferentiated phenotype which is further altered by mutation.

Unlike most studies which only give the stromal microenvironment a cursory nod, this project gives it a starring role. It’s a world away from the traditional cancer cell-centric view of malignancy, repositioning the disease as the sum total of a complex web of interactions between tumour and host.

The team’s ultimate goal is to develop a new class of therapeutics which hacks into this circuitry to restore or mimic normal stromal cues.

First, deconstruct the stroma

The Tlsty team comprises a constellation of world-class scientists from across the physical and biomedical sciences. This unique cocktail of expertise will build – for the first time – a truly panoramic view of the stromal contribution to tumorigenesis.

First, they’ll determine the cellular and molecular composition of tissue from four organs (oesophagus, colon, stomach and lung) as they progress along the continuum from healthy to malignant states using a myriad of techniques including single-cell RNA analysis, atomic force microscopy to measure tissue mechanics, and ECM proteomics.

A key feature of this work package is the deployment of a new technology – pioneered in-house – called CODEX, which inexpensively converts fluorescence scopes into high dimensional imaging platforms, allowing for multiplex image analysis on an unprecedented scale. CODEX will enable the team to deconvolute individual cell populations within a tissue, allowing them for example to uncover patterns of immune cell infiltration associated with progression towards a more malignant phenotype.

Community building

The single-cell transcriptomic data will be used to develop maps of tissue-tissue interactions and the functional implications of these intercellular communication networks will be predicted with mathematical models.

Combined with CODEX, which will allow these communities to be resolved spatially, the results will allow the team to chart – in both space and time – crucial control points that stabilise or undermine different tissue states.

Borrowing from developmental biology, these tissue interactions will be interrogated in vivo and in vitro using a technique called heterotypic tissue recombinant models, where epithelial cells are cultured with defined stromal or mesenchymal cell populations, and their effects on cell fate and tumorigenic potential recorded.

The team will test this approach with traditional cell cultures and genetically engineered mouse models. And they’ll be harnessing novel ‘organ-on-a-chip’ microfluidic devices which mimic the more complex properties of organs such as mechanical motion, interactions with endothelial cells, fluid flow and more.

By adding or subtracting different cellular components, they will be able to define the critical go/no go points along the malignant pathway worth targeting.

New ideas...

Unlike most cancer therapeutics which target the malignant cells, the team believes that focusing on reprogramming the stroma could prevent or reverse malignant transformation.

Putative targets will be cross-referenced against libraries of known compounds and will be used to drive novel computer-assisted drug discovery approaches. Promising hits will be rapidly tested in the numerous models developed by the team. These strategies will sit alongside the pre-clinical testing of compounds that have already been identified by team members to be stromal modifiers.

They will also explore whether cells might be engineered to sense and neutralise inflammation through the delivery of customised payloads such as immune stimulators or cytokines, thereby effectively mimicking the body’s own response to injury or infection.

The team is also committed to finding biologically-driven solutions to the problem of patients with pre-malignant conditions such as Barrett’s oesophagus (BO) where the resident squamous epithelia of the oesophagus to be replaced by columnar epithelia. The trigger for this metaplastic response is believed to be injury caused by acid reflux.

A small percentage of people with BO go on to develop oesophageal adenocarcinoma (OAC), but in these unlucky few, BO follows a predictable (yet poorly understood) trajectory; metaplasia, dysplasia and finally OAC. By using CODEX to analyse serial samples of patients with BO, the team hopes to develop a palette of biomarkers which will predict those who are likely to progress and develop cancer, from those who are not.

... for an old problem

The story of cancer and inflammation goes back to 1863 when the German pathologist Rudolf Virchow observed immune cells in his tumour samples. The observation led him to propose that inflammation was a driving force in cancer – a theory that was largely ridiculed by his peers.

Virchow will never know that over 150 years later, Grand Challenge has given Tlsty and her team the opportunity to tackle his renegade hypothesis on an unimaginable scale. As Tlsty states: “When you have what Grand Challenge has offered, it allows you to think big and to think way beyond the little incremental steps forward. It lets you jump to something that could be well and truly different.”  

Margaret Grayson, Grand Challenge Patient Panel 

"It has been exciting to be part of the patient advisory panel; this project could have a massive impact on the lives of people with cancer. Thank you Cancer Research UK for enabling this type of blue sky thinking to become a reality." 

Prof. Ed Harlow introduces Prof. Thea Tlsty's Grand Challenge

Chronic inflammation is involved in 1 out of 4 cancers, killing 1.7 million people worldwide annually. Yet, the role of chronic inflammation in the transformation of healthy cells into cancer cells remains poorly understood. Our team is excited to use pioneering approaches and tools to solve this puzzle, and to apply this knowledge toward preventing or reverting these cancers, hoping to improve treatment for those suffering with these diseases.

Professor Thea Tlsty, Principal Investigator

The team

 

Professor Thea Tlsty

Principal Investigator
Professor of Pathology

Country: USA
Organisation: University of California, San Francisco (UCSF)
Discipline: Molecular pathology

 

Professor Uri Alon

Professor of Systems Biology

Country: Israel
Organisation: Weizmann Institute of Science
Discipline: Systems biology

 

Professor Sui Huang

Professor of Systems Biology

Country: USA
Organisation: Institute for Systems Biology, Seattle
Discipline: Systems biology

 

Lorenzo Ferri 

David S Mulder Chair in Surgery, Professor of Surgery and Oncology

Country: Canada
Organisation: The Research Institute of the McGill University Health Centre

 

James R. Goldenring

Paul Sanger Professor of Experimental Surgery and Co-Director, Epithelial Biology Center

Country: USA
Organisation: Vanderbilt University Medical Center
Discipline: Gastric pre-cancer biology

 

Professor Donald Ingber

Judah Folkman Professor of Vascular Biology, Professor of Bioengineering and Founding Director of the Wyss Institute

Country: USA
Organisation: Wyss Institute for Biologically Inspired Engineering at Harvard University
Discipline: Bioengineering

 

Dr Stuart McDonald

Senior Lecturer in Tumour Biology

Country: UK
Organisation: Barts Cancer Institute, Queen Mary University of London
Discipline: Gastroenterology

 

Professor Garry Nolan

Rachford and Carlota A Harris Professor of Microbiology and Immunology

Country: USA
Organisation: Stanford University
Discipline: Microbiology, immunology

 

Professor Morag Park

Director, Rosalin and Morris Goodman Cancer Research Centre

Country: Canada
Organisation: McGill University
Discipline: Cancer genetics​

 

Dr Kole Roybal

Assistant Professor in Microbiology and Immunology

Country: USA
Organisation: University of California, San Francisco (UCSF)
Discipline: Microbiology, immunology

 

Dr Doug Winton

Group Leader

Country: UK
Organisation: Cancer Research UK Cambridge Institute
Discipline: Cancer biology, stem cell biology

 

Desiree Basila

Patient Advocate

Country: USA
Organisation: Patient Advocates In Research (PAIR)
Discipline: Genetic counselling

 

Deborah Collyar

Patient Advocate

Country: USA
Organisation: Patient Advocates In Research (PAIR)

 

Ann Russell

Patient Advocate

Country: UK
Organisation: Affiliated to the Cancer Research UK Cambridge Cancer Institute; National Cancer Research Institute Consumer Forum; independent cancer patient voice

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