Study reveals molecules enabling bowel cancer to hijack healing processes and spread
Scientists have uncovered how bowel cancer cells imitate our gut’s natural healing processes to adapt, spread and grow. The findings by Dr Mirjana Efremova and her team at Barts Cancer Institute (BCI), Queen Mary University of London, published in Cell Genomics, could lead to new treatment strategies aimed at preventing cancer spread.
“Bowel cancer is the second deadliest cancer globally,” explains Dr Mirjana Efremova, senior author of the new study. “This is due partly to these cells’ ability to change and adapt, allowing the disease to spread, evade treatment and eventually recur.”
Our gut is constantly repairing itself due to damage from food, digestive substances and microbes. Stem cells within the gut produce new cells to replace injured ones, while other gut cells can also revert into a stem-cell-like state and switch on processes that aid regeneration.
Previous studies have suggested that bowel cancer cells can imitate this regenerative process, enabling them to adapt, multiply and spread. These regenerative cancer cells act as pioneers of cancer spread (metastasis) and help to recreate the tumour in a new part of the body, potentially providing an important target for therapies designed to halt disease progression.
"This study gives us a good indication of what is driving these cells’ regenerative state."
— Dr Mirjana Efremova
However, while this phenomenon has been examined in animal models, very little was known about how it occurs in human cancers. To bridge this gap, researchers led by Dr Efremova and first author Dr Sam Ogden at BCI explored the factors controlling how bowel cancer cells adapt and spread to the liver, using human tissue samples from the Barts Cancer Tissue Bank.
The team used cutting-edge techniques known as single-cell multiomics, which examines the molecular activities of individual cells, and spatial transcriptomics, which maps the activities of cells in different locations within tissues. They studied patient samples from the primary tumour site in the bowel and metastatic tumours in the liver.
The researchers discovered that human colorectal cancer contains regenerative cells that closely resemble those previously described in laboratory models as pioneers of metastasis. They also identified an intermediate cell state between regenerative cells and stem cells, indicating the ability for one type to transition into the other.
“This is important because it tells us that in order to target these cells with a drug, you need to target both at the same time, otherwise one cell can simply convert to become the other.” Dr Efremova explains.
To explore exactly what drives this regenerative ability in cancer cells, Dr Ogden studied patient-derived organoids—mini-tumours grown in the lab from patient cells. His research revealed two key molecules, AP-1 and NF-κB, which switch on genes responsible for the regenerative properties in these cancer cells.
“The regenerative cells in our organoids were sensitive to a class of drug called MAPK inhibitors,” explains Dr Ogden. “This suggests there might be ways to target these cells, possibly through a combination of therapies.”
The team also analysed the local environment surrounding these regenerative cells. They found that the cells reside within an immune-suppressive microenvironment, which helps to maintain their regenerative state. In future research, they plan to disentangle the different signals involved in this process to better understand how these cells and their environment interact, potentially opening further opportunities to for the development of therapies that target these processes.
“This study gives us a good indication of what is driving these cells’ regenerative state,” Dr Efremova concludes. “While directly targeting AP-1 and NF-κB may not be feasible, upstream pathways or co-factors could present promising options for therapeutic strategies aimed at stopping bowel cancer from spreading.”
This work was made possible thanks to funding from Cancer Research UK and Barts Charity.
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