The stellar mission taking on cellular plasticity in bowel cancer

Much has been written about the dawn of molecularly targeted cancer therapy. But for people with bowel cancer, progress has been relatively slow compared to other common cancers. And that’s despite the disease’s major molecular pathways being mapped out decades ago.

Thankfully this is starting to change, with a string of recent discoveries revealing profound new insights into bowel cancer biology.

To translate these into new treatment approaches, a £5.5m consortium of international researchers has recently launched, and is injecting new, and much needed, momentum into the field.

Unmet need

In recent years, a handful of options have emerged to prolong survival for people with metastatic bowel cancer. For tumours that harbour mutations in the MAP kinase signalling pathway, patients can be offered combination therapy with BRAF/MEK and EGFR inhibitors, while those with ‘microsatellite-unstable’ tumours can benefit from immunotherapy. Nevertheless, none of these treatments can cure metastatic disease, and for people without these alterations, there are few options beyond conventional chemo- and radiotherapy.

That’s not for want of trying, according to Owen Sansom, director of the CRUK Scotland Institute in Glasgow, and a leading bowel cancer researcher. Efforts to replicate therapeutic successes seen in other tumour types such as lung, breast or melanoma have “proven frustrating”, he says. By the late 2010s, large, biomarker-stratified bowel cancer trials such as FOCUS4 had yielded largely negative results, while promising new biomarkers found by studies such as S:CORT had proven difficult to translate.

In 2018, these frustrations led Sansom, together with his long-term collaborator Simon Leedham, Professor of Molecular Genetics and a Gastroenterologist at the University of Oxford, to assemble a power-house collaboration of leading groups across the UK, Spain and Italy, funded by a Cancer Research UK Accelerator Award, to generate new model systems, and so uncover new approaches to treatment.

Across these teams lay the expertise to develop of a suite of clinically relevant bowel cancer models.

“So, in 2018, together with others from the UK bowel cancer research community, we formed what ultimately became a very successful consortium – ACRCelerate – to develop better bowel cancer models, including of metastasis.”

However, says Leedham, science being science, there was a twist: their “simplistic” idea – that these models would rapidly reveal molecular targets for therapeutic development – proved somewhat wide of the mark.

Instead, they revealed a profound new frontier in bowel cancer biology: cellular plasticity.

Plastic fantastic

The intestine has a well characterised population of adult tissue stem cells, situated at the base of the intestinal crypts and identified by a cell-surface receptor, LGR5.

However, over the course of their Accelerator Award, the team began to realise that these weren’t the only stem cells in the bowel. Instead, says Leedham, it became apparent that, in a regenerative setting, at least “two flavours” of stem cell emerged.

The implication was clear – any attempt to successfully treat bowel cancer would have to get around the inherent plasticity they were observing in their models. As their Accelerator Award funding reached its end, the consortium published a slew of transformative papers, including in Cell Stem Cell and Nature, revealing cellular plasticity as a key driver of bowel cancer recurrence and metastasis. “We showed that, in mice, if you deplete one population of stem cells within a tumour, the other expands, and starts to replace the lost population within about five to seven days,” says Leedham.

Collectively, their model data, and that from others working on bowel cancer, were painting a consistent and clear picture, of two distinct but dynamic stem cell states in bowel cancer – so-called proliferative cancer stem cells, analogous to ‘normal’ columnar stem cells, and a previously unrecognised ‘revival’ state, which seemed to exploit cellular programming used during regeneration, and – crucially – appeared to be resistant to therapy. And it was this latter state that appeared to drive recurrence and spread.

So, as their award was coming to an end, two key questions presented themselves: does this phenomenon drive bowel cancer in humans? And if so, how could it be exploited therapeutically? Finding answers meant going beyond their models, and looking in clinical samples of bowel cancer, ideally pre- and post-therapy.

Dancing the FOxTROT

While ACRCelerate collaborators had been revealing cellular plasticity in their model systems, clinically, the picture had been evolving too. In Leeds, Jenny Seligmann had been part of the team behind a clinical trial, FOxTROT, that by 2023 had demonstrated clear benefits of neoadjuvant chemotherapy among some patients with stage 2 and 3 bowel cancer.

Building on the trial’s success, with collaborators in Birmingham, Seligmann set up the FOxTROT platform to investigate further. “We know there are patients having ineffective treatment in the curative setting for bowel cancer. FOxTROT is looking to tackle that by investigating new neoadjuvant treatment options,” says Seligmann. But alongside this, she says, “there’s a real need to understand the science behind why they’re not responding.”

Funded by Yorkshire Cancer Research and industry partners such as GSK, FOxTROT now has five separate arms, each investigating a different approach to neoadjuvant treatment – but all united by a common approach to collecting vital pre- and post-treatment tissue samples, bloods and clinical data. So far, over 500 people with locally advanced, operable bowel cancer have been recruited. And this, Sansom and Leedham reasoned, formed an ideal platform to validate stem cell plasticity, and test hypotheses emerging from model systems.

“When we approached Jenny and her team, it turned out that they needed funding to help support the analysis of the samples,” says Sansom. It was an ideal partnership – and with ACRCelerate’s funding soon to end, the trio got together to plot a path forward.

“Owen and I went to Leeds, where Jenny had booked a meeting room in a hotel near the station, and we sat down with a flipchart for a day and figured out about how we should be writing this grant proposal,” recalls Leedham. “Owen and I had strong scientific ideas, but we needed to work out what samples are available, what were the right questions to ask, and whether they have clinical rationality. Jenny was able to steer us in the right direction, and marshal all the people involved in running the trials.”

The result, funded by Cancer Research UK, the Bowelbabe Fund for Cancer Research UK, and the Scientific Foundation of the Spanish Association Against Cancer (FCAECC), together with philanthropic support from Bjorn Saven CBE and Inger Saven, is a hugely ambitious, comprehensive bowel cancer study. Known as ColoRectal Cancer Stratification of Therapies through Adaptive Responses, or CRC-STARS, it’ll integrate cutting-edge discovery science with clinical and translational approaches.

Reach for the STARS

As well as teams at Glasgow, Oxford and Leeds, the CRC-STARS consortium involves a constellation of researchers from around the UK, along with the teams in Spain who were involved with the original ACRCelerate programme.

“It means we’ll have clinical input from oncologists, pathologists and academic surgeons, working together with mathematicians, fundamental modelers, mouse experts and genomics experts,” says Leedham. We’ve also got the CRUK National Biomarker Centre on board to look at circulating markers. It is quite a large community, but people are so enthusiastic and keen to join in.”

Alongside the FOxTROT samples, the team has access to clinical samples collected during a study of neoadjuvant radiotherapy in rectal cancer called PRIME-RT, which recently showed that immunotherapy could enhance the benefits of radiotherapy. “The PRIME-RT team were able to collect serial biopsies over the course of the study,” says Sansom. “Our preclinical data shows that irradiation drives LGR5⁺ stem cells into the revival state, so it will be fascinating to look at these samples to see if that’s occurring.”

With access to so many samples, each of which being a limited, precious resource, a clear plan to analyse them has been vital. “We’re basically aiming to take advantage of the spatial revolution,” says Sansom.

“We need to get as much information from these biopsies as possible. So we’re doing a lot of spatial biology, including using COSMX for whole transcriptome analysis, but also very bespoke Xenium panels, which allows us to look at 300 of our key targets. We’re also using state-of-the-art sequencing which we can now do on formalin-fixed archival samples, to look at whole genome, mitochondrial mutations, and methylation. And because we can look at how everything changes pre- and post- treatment, and cross-validate in our model systems, there’s so much biology we can learn.”

The logistical feat of carrying out all these analyses won’t be trivial. “The thing with CRC-STARS is not to underestimate the amount of work that goes into preparing trial samples to be sent for sequencing,” says Seligmann, “So a lot of our work will be just making sure that all practical pieces are in place. It’s also vital to make sure we’re selecting samples most likely to yield the answers to the questions that we’re trying to answer.”

The key thing, she says, is that they’ll be able to go from “bedside, to bench, and back to bedside”, validating results in laboratory models, then using the resulting findings to re-interrogate the clinical data. “The exciting thing will be how we interpret the results. To ask how they fit into the landscape of bowel cancer management, and how can we then translate what we’re learning into the next FOxTROT study for patients with the disease?”

“It was a big piece of work trying to get everybody together, trying to make sure we were agreeing on technology platforms, on what we’re doing with all the samples, prioritising samples,” says Sansom. But he thinks the answers could be profound. “I’m hoping that we will reveal the cellular landscape of response and non-response in bowel cancer, in different therapeutic contexts. And I think over the next two or three years, we’re going to learn more about human bowel cancer responses than ever before with all these cohorts.”