Could changes to our guts as we age give cancer the edge?

Why focus on fibroblasts?

My lab has been working on fibroblast biology for a long time, examining the activity of these ubiquitous tissue cells in diseases such as chronic inflammatory disorders and cancer. We know that fibroblasts play an important role in maintaining the balance between health and disease in bodily tissues. But there are gaps in knowledge about their roles in the gut, particularly in age-related gut diseases. There are significant differences in expression profiles of aged intestinal fibroblasts compared with those in younger intestines. We believe that age-related dysbiosis and gut permeability could fuel these changes in fibroblasts, which may in turn generate a microenvironment favourable to carcinogenesis. We know that fibroblasts in gut tissues can sense and respond to innate immune signals, and that they interact with certain microbial products. But very little is known about these specific interactions. For example, we don’t know whether microbes and fibroblasts interact directly, whether changes in gut microbiota drive the changes we see in fibroblasts during ageing, or whether these microbially-driven cellular changes then predispose a person to develop colorectal cancer.

What are the main aims of your GGGH project?

Cancer is a disease of old age, especially colorectal cancer, which becomes more prevalent after the age of 60. We want to examine how age-related changes in the microbiota influence intestinal cells and how this in turn impacts health and disease states. We hope to identify the molecular changes that occur in gut tissues before carcinogenesis. We will use stromal organoid (three-dimensional cellular models that mimic organ functions) co-cultures to determine the most likely molecular mechanisms at play, alongside collecting extensive data from mouse models and comparing these findings with existing human data sets. We will then verify our findings using human samples. We’re hoping to pinpoint key molecular markers that could be used for early cancer prognosis or even developing preventative measures.

What triggers age-related dysbiosis?

An important difference between a youthful gut and an ageing gut lies in microbial diversity — our guts tend to become less microbially diverse as we age, particularly if we suffer from inflammation and disease. Many parameters can influence age-related dysbiosis including diet, medication, and reduced physical activity. Dysbiosis can also be caused by subtle changes in the networks of interactions within the gut, including how the host immune system and associated inflammation alter microbial activity. Chronic inflammation can increase the permeability of the intestinal barrier — this means that microbial products, and even the microbes themselves, breach the barrier and are found inside host mucosa. There, they interact with and influence the activity of host cells, including fibroblasts. It’s not yet clear how each factor influences disease prognoses.

How do you disentangle these processes in a complex gut system?

It’s not easy. We will gather a vast amount of data that shows how microbes change, how metabolites change, and how tissues change at the cellular level during ageing. We will then build networks of interactions, particularly between microbes and fibroblasts. Once we’ve created these interaction networks, we will test them in vitro to see if they hold true. If we can verify these interactions, then we will do in vivo experiments and validate them there. We will go from the broader picture down to very specific micro-interactions, and build a strong overall idea of how microbes, metabolites and host fibroblasts behave in the gut network. One of the biggest challenges will be combining all the high-throughput, inter-species data. Ultimately, we want to understand the genesis and progression of diseases in humans, and so accurately translating the results from animal models into the human context is very important.

How will organoid models help?

Organoids have transformed the way we work — they mimic real life, allowing us to model and understand the intricacies of biological systems in far more detail than in traditional two-dimensional cell cultures. Organoids are miniature, cellular models of a given organ, wherein the cells create a three-dimensional structure that looks and behaves in a very similar way to the organ in vivo. This allows us to explore the tissue matrix and interactions within that organ given certain parameters. We are using both intestinal organoids and tumour organoids in this project. We are particularly keen to see how changing fibroblasts affects the properties of intestinal stem cells in ageing gut tissues, and also how fibroblasts may affect tumour proliferation and growth. We plan to elucidate molecular mechanisms and examine these working hypotheses in the mouse models using faecal microbiota transplants.

Why use faecal microbiota transplants?

This is an established, straightforward way to see how different microbiota compositions can directly affect the gut tissues. You take faecal samples from old mice and implant them into young mice, and monitor what happens at the cellular level in gut tissues. You can also do this in reverse, giving microbiota from young mice to older mice. This can help us determine whether there are properties of the ageing intestine that are influencing disease states, but don’t have anything to do with the microbiome.

What practical applications could your results have?

By identifying specific molecules and signalling pathways that could affect tumorigenesis in the ageing gut, we believe we can pinpoint markers for early prognosis. Just because a person is 60 years old, does not mean that their gut is 60 years old — every person is unique. The speed of ageing varies considerably between individuals, and can even vary between organs within one person’s body depending on what has occurred during their lives. We hope to identify specific factors that could lead to early cancer detection, or highlight elevated risks. The development of preventative measures can follow.

Biography

Vasiliki Koliaraki is a biologist and research associate professor at the Biomedical Sciences Research Center ‘Alexander Fleming’ in Vari, Greece. She established her lab in 2016 and has since focused on studying the biology of fibroblasts and their role in intestinal homeostasis and disease pathogenesis. This work has led to several publications describing the molecular pathways that regulate inflammation and cancer in the intestines. Her team uses genetic engineering in mice, animal models of intestinal disease, high-throughput analyses, and organoid co-cultures to identify fibroblast-specific aetiopathogenic mechanisms. She will use these approaches to understand the role of age-associated dysbiosis on fibroblast properties and downstream functions in the ageing intestine.