New research from the Dana-Farber Cancer Institute demonstrates that the cells in the lining of the colon can go through a transition before cancer develops. Using mouse models and tumor models called patient-derived organoids, researchers discovered that the cells undergo a type of molecular time travel that reverts them back to an embryonic state. The researchers also uncovered that this “time travel” depends on a protein called Sox9.

The findings are published in Science Advances in an article titled, “Aberrant cell state plasticity mediated by developmental reprogramming precedes colorectal cancer initiation.”

“Cell state plasticity is carefully regulated in adult epithelia to prevent cancer,” the researchers wrote. “The aberrant expansion of the normally restricted capability for cell state plasticity in neoplasia is poorly defined. Using genetically engineered and carcinogen-induced mouse models of intestinal neoplasia, we observed that impaired differentiation is a conserved event preceding cancer development.”

The current study looks at what happens before the emergence of these mutations and finds not only evidence of fetal reprogramming that can initiate cancer, but also a protein, Sox9, that fuels that reprogramming. This and previous research from the lab of Nilay Sethi, MD, PhD, suggest Sox9 is a promising therapeutic target for colorectal cancer.

“Genetic inactivation of Sox9 prevented adenoma formation, obstructed the emergence of regenerative and fetal programs, and restored multilineage differentiation by scRNA-seq,” noted the researchers. “Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.”

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