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 Cancer Grand Challenges 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, Cancer Grand Challenges has given Tlsty and her team the opportunity to tackle his renegade hypothesis on an unimaginable scale. As Tlsty states: “When you have what Cancer Grand Challenges 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.”