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Vanderbilt University Medical Center Reporter

Study explores less invasive way to monitor colorectal cancer

by Lorena Infante Lara

Investigators at Vanderbilt University Medical Center have published research regarding an important feature of colorectal cancer (CRC) that could eventually lead to the development of non-invasive means of monitoring cancer progression. After lung cancer, CRC is the second-most lethal cancer in the United States.

The team’s research, published in eLIFE, indicates that colorectal cancer cells release tiny RNAs called microRNAs (miRNAs) so as to make their environment more permissive to their growth.

Virtually all cells can release their cellular contents through small, bubble-like vesicles called exosomes. Exosomes were thought to be disposable “trash bags” for cells when they were initially discovered, but further research has pointed to an additional role in cell-to-cell signaling. Colorectal tumors have been shown to use exosomes to help facilitate metastasis.

Although proteins and RNA are present within the exosomes, the function and importance of the RNAs has remained unclear. The Vanderbilt research challenges the previous way of thinking by looking at the miRNAs that cancer cells secrete.

These miRNAs are designed to bind to target mRNAs, the middle step in the production of protein from the DNA, and usually lead to lower expression of their cognate proteins. The Vanderbilt group hypothesized that miRNAs, which have been found in exosomes, might enact a regulatory function by altering gene expression patterns in recipient cells. The idea that secreted RNAs might signal between cells is the focus of a new NIH-funded Extracellular RNA Communication (ERC) program and the Vanderbilt group is one of five teams leading this consortium.

The Vanderbilt team was led by Robert Coffey, M.D., Ingram Professor of Cancer Research, James Patton, Ph.D., Stevenson Professor of Biological Sciences, and Alissa Weaver, M.D. Ph.D., Professor of Cancer Biology, and included Jeff Franklin, Ph.D., research assistant professor of Cell and Developmental Biology, and Diana Cha, a graduate student in Patton’s lab.

“Going in, we knew that proteins were going to be important,” Franklin said, “but we didn’t know that RNAs were going to function in this system. It was a pretty questionable idea.”

The investigators looked at secreted RNAs in colorectal cancer cells with either the wild type or mutated version of the KRAS gene, which codes for a protein that is involved in normal cell signaling. Mutations in KRAS play an important role in the development of cancer; in fact, nearly 40 percent of patients with CRC have a mutation in KRAS.

Coffey’s lab had previously reported that mutant KRAS leads cancer cells to secrete tumor-promoting proteins in their exosomes. In this latest study, they found that mutant KRAS also affect which miRNAs are packaged and released in exosomes. These miRNAs were found to downregulate target mRNAs in healthy recipient cells that could promote the growth of the cancer cells.

Although it seemed like a long shot that miRNAs would be differentially sorted into exosomes depending on the status of a single gene, the authors’ ventures paid off. For the first time, there is evidence that dysregulation of miRNA secretion plays an important role in cancer development.

“A lot of people in the field wondered, ‘Why are you looking at RNA? You should be looking at protein.’” Franklin said.

In the future, monitoring cancer progression could be as simple as taking a blood test that sequences the RNA in exosomes in lieu of more invasive techniques.

Beyond CRC, exosomes might also serve as useful biomarkers in other diseases and even drug addiction.

“If everyone hasn’t already started thinking if exosomes play a role in their research, they should start thinking about it,” Cha said.

The research was supported in part by the National Institutes of Health as part of the Extracellular RNA Communication Consortium (grant number CA179514).




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