Few areas of the body face more daily stress and potential damage than the stomach, which must manage everything we swallow. Along with this constant strain, the stomach also produces acid that can damage its own lining and increase the risk of ulcers.
To keep up, the stomach lining has remarkably high regenerative rates, continuously replacing cells and repairing damage as it occurs. This cycle, while essential, activates pathways linked to tumour development — gastric cancer being one of the most common and fatal diseases in the world.
"Cancer can develop from abnormal regeneration, so it is vital that the body stops the process properly and restores cell identity and function in the stomach," says Dr. Tae-Hee Kim , Senior Scientist in the Developmental, Stem Cell & Cancer Biology program at The Hospital for Sick Children (SickKids).
"But the mechanisms that regulate tissue restoration have long been unclear, so we decided to focus on this puzzle in the stomach environment, believing it may be key to cancer prevention."
Surprising results lead to new understanding
Members of the Kim Lab used single cell 10x multiome technology available through The Centre for Applied Genomics to study what happens inside stomach cells during healing and recovery Together with the Rhee Lab at the University of Toronto, they analyzed the interplay of gene expression and DNA regulation within the same stomach cell during various states of regeneration and recovery.
After observing unexpected results, the team discovered the biological processes that regulate gene expression (which specific genes are turned on or off) in gastric regeneration, recovery and cancer. Their study, published in Developmental Cell, highlights how certain conditions and responses in the stomach make it vulnerable to cancer.
First, the team identified that the BRG1/BRM-Associated Factor (BAF) chromatin remodeling complex is active during recovery. Inside the BAF complex, they deleted Arid1a, which is among the most altered genes in gastric cancer, but whose role in regeneration and recovery is unknown.
"We expected to see tumours begin to form, but that was not the case," says Adrian Loe, first author and postdoctoral fellow in the Kim Lab. "Instead, deleting Arid1a after an injury to stomach cells left them in a persistent state of regeneration, unable to recover."
What this suggests is that Arid1a plays a critical role in cell recovery in the stomach. After weeks of these cells remaining in this unresolved regenerative (yet cancer-free) state, the researchers then removed Trp53, the most common gene tied to cancer. Doing this, in an environment marked by a loss of Arid1a, was sufficient to trigger cancer and cause it to spread.
Exposing the importance of understanding cell recovery
These new findings suggest that genetic variants tied to cancer are not acting on their own but instead depend on what's happening in the surrounding environment. The study shows that while the process of regeneration and healing can raise the risk of stomach cancer, incomplete recovery increases that risk much further.
"Regenerative medicine is a dynamic and fast-moving area of research, but we can't lose sight of the fact that we need to better understand how to control regeneration as well," Kim says. "That's because, as our study showed, it opens a susceptibility to cancer.
"As the field of regenerative medicine advances, we must also focus on studying how the conditions that return to a healthy, balanced state."
This study was supported by the SickKids Restracomp fellowship, Ontario Graduate Scholarship, Canada Graduate Scholarship; Natural Sciences and Engineering Research Council of Canada, Canadian Institutes of Health Research (CIHR) and the the Garron Family Cancer Centre Pitblado Discovery Grant.
