How can chimeric, droplet-forming proteins contribute to cancer?

BUFFALO, NY — In the run-up to cancer, genetic mutations can sometimes lead to the formation of chimeric proteins made from parts of two different proteins that are usually separated.

A new review article examines the latest science on a particular class of these cancer-associated “oncofusion proteins,” targeting those oncofusion proteins that can form fluid-like droplets called “ectopic condensates” in cells.

The article was published on April 25 in Trends in Cell Biology by University at Buffalo researchers Richoo B. Davis, Mahdi Muhammad Moosa, and Priya R. Banerjee, all in the Physics Department of the UB College of Arts and Sciences. Banerjee, PhD, is an assistant professor of physics, and Davis, PhD, and Moosa, PhD, are postdoctoral associates in the Banerjee Lab.

In lab experiments, ectopic condensates form when part of a protein that normally forms droplets fuses with part of another protein usually found in a different location in a cell. The resulting chimeric protein retains some of the functions of both parent proteins and is able to form droplets in the “wrong” place in cells, Moosa says.

Protein droplets, also called “membraneless organelles,” may serve as junctions of biochemical activity, so misplaced droplets with aberrant functions are interesting to investigate, the researchers say.

“A key audience for our review is cancer researchers,” says Moosa. “Biophysicists studying biomolecular condensates may already be familiar with these concepts, but we wanted to achieve and share these insights with cancer biology researchers working directly with patient samples.”

Davis notes that ectopic condensates may be an attractive target for cancer therapies, but more research is needed to better understand how these chimeric proteins work in their natural state and how they can rewire gene transcription that leads to cancer development: “The cell is a very complex system,” he says. “We need better tools to study protein condensates in their native conditions, and our future studies will focus on this.”

In the review article, the authors summarize emerging findings from multiple recently published works from various research groups, including a 2021 study they completed together with Taranpreet Kaur, a recently graduated UB physicist.

That earlier article, which appeared in a special issue of the magazine protein science on “Biophysics of Biomolecular Condensates,” focused on a FET family oncofusion protein and was titled, “FUS Oncofusion Protein Condensates recruit mSWI/SNF chromatin remodeler via heterotypic interactions between prion-like domains.” The team showed how these ectopic protein condensates can recruit key molecular machines to alter the balance of gene regulation.

“The discovery of protein phase separation has changed our view of how cells organize their internal space,” Banerjee says. “As more and more research in this exciting field emerges, we are learning about the role of protein droplets in important biological processes such as gene regulation and their role in fatal human diseases. Based on the emerging data from several labs, we suspect that a subset of cancer-linked fusion proteins can form new types of condensates that normal cells do not have.”

“The study of naturally occurring fusion proteins and their condensates with new biological functions is important not only from a cancer biology perspective, but also from a protein engineering perspective, because learning how these fusion proteins work will open up new possibilities to create artificial proteins. new applications in the biomedical sciences,” Banerjee added.

Research in the Banerjee Lab is supported by grants from the National Institute of General Medical Sciences, National Institute on Aging, and National Center for Advancing Translational Sciences, all part of the National Institutes of Health, along with the Mae Stone Goode Trust and UB University of Applied Sciences. Arts and Sciences.