Penn Vet researchers pinpoint new driver of colon cancer

Genetic research has advanced our understanding of how and why cancer occurs by identifying mutations that are associated with an increased risk of getting the disease or with more aggressive forms of cancer.

But mutations in the DNA code are not the only explanation for why cancer occurs. In a new study, researchers from the School of Veterinary Medicine point to an RNA-binding protein as a significant contributor to driving colorectal cancers, a leading cause of cancer-related deaths worldwide.

The responsible gene, MSI2, is not directly mutated in cancer; rather, it becomes highly expressed in tumors with a variety of underlying genetic mutations. Then, by binding to RNA, it affects how much of certain proteins are made, leading to uncontrolled cellular growth.

The research, which was published this week in Nature Communications, was headed by Christopher Lengner, an assistant professor in Penn Vet’s Department of Animal Biology. He became interested in MSI2 years ago, when studies showed that it was associated with the ability of stem cells to differentiate into a variety of cell types, and was also highly expressed in blood cancers.

The study observed that MSI2 is almost universally over-expressed in colorectal cancers in comparison to healthy tissue. To learn more about how MSI2 functions in the body, the researchers used human colorectal cancer cell lines and animal models in which they could manipulate MSI2, either experimentally increasing or decreasing its levels. They found that blocking MSI2 in cancer cells blocked tumor growth, while activating it in mice cause the animals’ cells to stop differentiating and proliferate uncontrollably, resulting in death within just a few days.

“These mice look very similar to those that lack the tumor suppressor gene called APC, which is a major susceptibility gene in colorectal cancer,” Lengner says.

Further investigations illuminated MSI2’s place in a key molecular pathway involved in promoting tumor growth. Using a cutting-edge technique, the Penn team was able to catalog all of the RNA molecules that MSI2 binds to in living tissue, discovering that MSI2 can inhibit several RNAs that encode tumor suppressor proteins. When it is activated, MSI2 inhibits these tumor suppressors and amplifies the activity of a protein complex called mTORC1 that normally tightly regulates how cells obtain nutrients and growth factors.

“This enables the uncontrolled growth that culminates in the formation of aggressive tumors,” Lengner says.

The findings offer researchers a potential new target for colorectal cancer therapies, and may help in solving the puzzle of why cancers can come back after years of apparent remission.

“This is really where we’re heading, to see whether MSI2 has a role in possibly allowing cancers to remain hidden in the body,” Lengner says. “That is a big black box.”

Colon Cancer