Notre Dame Team Identifies New Cancer DNA Transfer Pathway

University of Notre Dame researchers have discovered a previously unknown pathway by which tumor cells transfer genetic material to other cells in their microenvironment, contributing to cancer spread.

Unlike normal cells, cancer cells are often filled with cytosolic DNA, which is DNA found in the jelly-like fluid outside of the cell’s nucleus. This DNA can be derived from multiple sources, but recent evidence suggests that chromosomal instability is a primary source of cytosolic DNA in tumor cells.

The team discovered that DNA “cargo” is transported in small informational sacs called extracellular microvesicles. “We’ve shown that DNA present in these microvesicles is related to metastasis, so now we have a great platform to assess for genetic aberrations,” says Crislyn D’Souza-Schorey, the Morris Pollard Professor in the Department of Biological Sciences.

The research team used a cell model from a male cancer patient to show how Y-chromosomal DNA—present in the cytosol due to chromosomal instability—is carried by extracellular vesicles and transferred to a female mammary epithelial cell line. “These female cells do not have Y-chromosomal DNA present without exposure to the male microvesicles,” says James Clancy, research assistant professor of biological sciences and coauthor. “This is an accessible way to show people that the DNA was transferred, making it easier to prove this form of communication.”

The researchers also showed that cytosolic DNA is moved to microvesicles alongside an enzyme, cGAS, which was discovered in part because of its role during the immune response to bacterial and viral infections. Scientists have increasingly recognized that cGAS may play a part in tumor progression, and this new study described a pathway in which the DNA is modified to aid that progression.

Work published by D’Souza-Schorey’s lab in 2019 in Nature Cell Biology described how microRNA within tumor cells is moved to microvesicles just beginning to form at the cell periphery. Once shed, these vesicles are taken up by non-tumor cells in the microenvironment. Microvesicles can also be found circulating through the body in fluids like blood and urine, and can be used as biomarkers that point to the presence of cancer.

While microRNA can affect protein expression more quickly than DNA, the researchers were interested in the DNA content as it is the actual part of a person’s genome, including any tumor-associated mutations, Clancy said. It was also more difficult to prove that DNA moved from one cell to another.

The findings were published in Cell Reports and build on the lab’s previous work investigating how information is shared between cells. Further foundational work on the topic could lead to early detection of different types of tumors.