It may be time to rethink the genetic foundation of colon cancer. New research is challenging the notion that the Wnt pathway is held responsible for the majority of colon cancer cases in humans. Instead, researchers at the University of Pennsylvania are reporting in the journal Cell Reports that the Musashi genes, MSI1 and MSI2, act in a path parallel to the Wnt pathway and may be equally important for driving colon cancer.
“The data suggest that either MSI protein is sufficient to support cancer,” said study investigator Christopher Lengner, PhD, BS, who is an assistant professor in the Department of Biomedical Sciences in Penn’s School of Veterinary Medicine, in a news release. “If you want to use these proteins as a drug target, you’d have to design a drug that will inhibit both of them.”
The work indicates that the two genes, which encode RNA-binding proteins, are functionally redundant. While researchers have known for some time that MSI1 was expressed in colon cancer, the mechanism by which it acted and its functional requirement for the disease were not well understood. The related MSI2 protein had not been rigorously examined in the context of colon cancer until recently when it was found that it could trigger activation of cellular metabolic processes that fuel cancerous cells in the intestines.
The current work took both proteins into account and it found that MSI1 was more variable and overexpressed in some samples, and underexpressed in others compared to normal tissue. The current analysis revealed that activating MSI1 caused a set of genes to be expressed that match the effect of losing the function of APC, a tumor suppressor gene that is inactivated in more than 80% of cases of human colon cancer.
To confirm whether both MSI1 and MSI2 are necessary for tumor formation, the researchers inhibited one or the other, or both in several human colorectal cancer cell lines. They found that inhibiting only MSI1 blocked growth of some cell lines, but not others. However, inhibiting both MSI1 and MSI2 together effectively blocked cell growth in all of them.
Adding an inhibitor of β-catenin, the downstream mediator of the Wnt pathway, synergized with MSI inhibition to completely block tumor cell growth. However, Lengner said by deleting both MSIs, the researchers found that it completely blocked the tumors from forming. He also noted that blocking the mTORC1 pathway might be another viable strategy for targeting the downstream activity of the MSI proteins, perhaps in combination with an inhibition of Wnt/β-catenin, a pathway the researchers believe may act distinctly, but parallel to MSI activity.
“There are already mTORC1 inhibitors in existence, so one could imagine a combined approach could be an effective strategy,” said Lengner.