New Clues to Alzheimer’s Disease, Cancer and COVID-19?

Vanderbilt University Medical Center researchers have discovered a nanoparticle released from cells called a “supermer” that contains enzymes, proteins and RNA associated with multiple cancers, cardiovascular disease, Alzheimer’s disease and even COVID -19.

The discovery, reported Dec. 9, 2021, in Nature Cell Biology, is an important advance in understanding the role extracellular vesicles and nanoparticles play in transmitting important chemical “messages” between cells, in both health and disease.

“We have identified a number of biomarkers and therapeutic targets in cancer and potentially in a number of other disease states that occur in these superlakes,” said the paper’s senior author, Robert Coffey, MD. “What’s left to do now is figure out how these things are released.”

Coffey, Ingram Professor of Cancer Research and Professor of Medicine and Cell and Developmental Biology, is internationally known for his research into colon cancer. His team is currently investigating whether the detection and targeting of cancer-specific nanoparticles in the bloodstream could lead to earlier diagnoses and more effective treatment.

Cutline: Members of the supermere discovery team are (front row from left) Qi Liu, PhD, Robert Coffey, MD, Qin Zhang, PhD, and (back row from left) James Higginbotham, PhD; Dennis Jeppesen, PhD; and Jeffrey Franklin, PhD. (Photo by Erin O. Smith). Credit: Vanderbilt University Medical Center

In 2019, Dennis Jeppesen, PhD, a former researcher in Coffey’s lab and now a research instructor in medicine, used advanced techniques to isolate and analyze small membrane-enclosed extracellular vesicles called “exosomes.”

That year, another of Coffey’s colleagues, Qin Zhang, PhD, research assistant professor of medicine, devised a simple method using high-speed ultracentrifugation to isolate a nanoparticle called an “exomer,” which has no surface layer.

In the current study, Zhang took the “supernatant,” or liquid left over after the exomers were spun into a “pellet,” and spun the liquid faster and longer.

The result was a pellet of nanoparticles isolated from the supernatant of the exomeric spin — which the researchers called supermeres. “They’re also super interesting,” Coffey joked, “because they contain a lot of cargo previously thought to be in exosomes.”

For starters, supermers carry most of the extracellular RNA released by cells and found in the bloodstream. Among other functional properties, cancer-derived supermeres may “transfer” drug resistance to tumor cells, perhaps through the RNA payload they deliver, the researchers reported.

Supermeres are important carriers of TGFBI, a protein that promotes tumor progression in established tumors. Thus, TGFBI may be a useful marker in liquid biopsies for colorectal cancer patients, the researchers noted.

They also carry ACE2, a cell surface receptor that plays a role in cardiovascular disease and is targeted by the COVID-19 virus. This raises the possibility that ACE2 carried by supermeres may serve as a “bait” to bind the virus and prevent infection.

Another potentially important cargo is APP, the amyloid beta precursor protein involved in the development of Alzheimer’s disease. Supermeres can cross the blood-brain barrier, suggesting that their analysis could improve early diagnosis or possibly even targeted treatment of the disease.

“Identification of this rich abundance of bioactive molecules … raises interesting questions about the function of supermeres, and raises interest in the potential of these particles as biomarkers for disease,” University of Notre Dame researchers noted in a statement. review published with the newspaper .

Reference: “Supermeres are functional extracellular nanoparticles packed with disease biomarkers and therapeutic targets” by Qin Zhang, Dennis K. Jeppesen, James N. Higginbotham, Ramona Graves-Deal, Vincent Q. Trinh, Marisol A. Ramirez, Yoojin Sohn, Abigail C Neininger, Nilay Taneja, Eliot T. McKinley, Hiroaki Niitsu, Zheng Cao, Rachel Evans, Sarah E. Glass, Kevin C. Ray, William H. Fissell, Salisha Hill, Kristie Lindsey Rose, Won Jae Huh, Mary Kay Washington, Gregory Daniel Ayers , Dylan T. Burnette, Shivani Sharma, Leonard H. Rome, Jeffrey L. Franklin, Youngmin A. Lee, Qi Liu, and Robert J. Coffey, Dec. 9, 2021, Nature Cell Biology.
DOI: 10.1038/s41556-021-00805-8

Zhang, Jeppesen, and James Higginbotham, PhD, research instructor in medicine, are the first authors of the paper.

Other VUMC co-authors: Ramona Graves-Deal, Vincent Q. Trinh, MD, Marisol Ramirez, MS, Yoojin Sohn, Abigail Neininger, Nilay Taneja, PhD, Eliot McKinley, PhD, Hiroaki Niitsu, MD, PhD, Zheng Cao, MD , PhD, Rachel Evans, Sarah E. Glass, Kevin Ray, William Fissell, MD, Salisha Hill, MS, Kristie Rose, PhD, Mary Kay Washington, MD, PhD, Gregory Ayers, MS, Dylan Burnette, PhD, Jeffrey Franklin , PhD, Youngmin Lee, MD, PhD, and Qi Liu, PhD.

Research support included National Institutes of Health grants GM125028, CA218386, CA211015, CA197570, CA236733, CA241685 and CA229123, the Nicholas Tierney GI Cancer Memorial Fund and an American Heart Association Postdoctoral Fellowship.