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Medical School professors find target for cancer, Ebola

Protein involved in the growth, spread of cancer cells and virus identified

<p>Lysosomes break down extra materials in the cells. Cancer and Ebola can hijack this process, using the materials to support their own growth.</p>

Lysosomes break down extra materials in the cells. Cancer and Ebola can hijack this process, using the materials to support their own growth.

Christopher Stroupe, assistant professor of molecular physiology and biological physics for the Medical School, has found a potential target for the widespread treatment of cancers and, potentially, the Ebola virus: HOPS — a large multiprotein complex — tethering protein and the recycling function of the lysosome.

The lysosome is an organelle found in most animal cells that allows for the breakdown or digestion of cellular materials such as synthesized proteins, other organelles and even cells. HOPS plays a role in lysosomal function — namely the organelle’s fusion with the membrane-bound region known as the endosome. This fusion allows for cancer cells to recycle cellular materials, which allows cells to grow and survive.

HOPS offers an opportunity for targeting a core mechanism of survival for cancer cells.

“Over the last 10 years or so, there’s been a lot of work showing the connection between cancer and intracellular transport to the lysosome,” Stroupe said in an email statement. “The basic idea is that cancerous cells are enormously stressed because of their fast rate of growth and division. One strategy they use to survive is recycling used or damaged components in their lysosomes.”

Stroupe’s study — focusing on the potential role of HOPS as an oncological treatment target — received funding from the National Cancer Institute, a branch of the National Institutes of Health. Until this project, the main purpose of the funding was to identify and isolate human HOPS for future disease model studies.

“Up until now, all the work we’ve done on HOPS has been done using HOPS from yeast — the same yeast used to make bread, or beer or wine,” Stroupe said.

While model organisms, such as yeast, can allow insight into cellular mechanisms, results obtained from using them cannot always be translated to human systems. Neither cancer nor Ebola can alter yeast.

The NCI funding allowed Stroupe’s lab to purify and then utilize human HOPS, providing a better opportunity to place discoveries in a human context.

“I really want to emphasize how important basic, curiosity-driven research has been to this project,” Stroupe said. “The genes that encode HOPs were discovered in the 1980’s by several groups, working with yeast, that were just interested in the molecules that govern how material is sorted and delivered within cells.”

A few years ago, Lukas Tamm, professor of molecular physiology and biological physics, published a study examining the mechanisms for the Ebola infection, which focused on the virus infection cycle.

Biophysics represents a combination of molecular and cell biology, physics and chemistry. As Tamm described, it focuses on cellular mechanisms at a molecular level, leaning increasingly more towards a quantitative picture rather than a qualitative picture of the system. He and Stroupe similarly utilized this discipline in their independent studies.

“What we discovered a few years ago is that the protein that decorates the surface of Ebola virus changes its shape to a fist after it is internalized into infected cells,” Tamm said in an email statement. “This fist ‘punches’ its way into the cytoplasm and releases the Ebola genome into the cell for replication and making multiple progeny viruses. If this shape change could be inhibited by a drug, the disastrous Ebola virus infection cycle could be interrupted.”

Stroupe’s discovery, however, represents a potential for disruption at an earlier step in the same cycle.

“My faculty colleague Chris Stroupe very recently found small molecules that could interrupt this cycle at an earlier step in the process, namely on the journey of the virus to the endosome,” Tamm said. “[Stroupe] studies a large multiprotein complex called HOPS that is present in all eukaryotic cells from yeasts to humans, and found that some drug candidates interfere with HOPS’ action in intracellular vesicle trafficking that is required for Ebola virus entry and clearance of cancer cells.”

Stroupe sees the potential for additional research for human HOPS, as there is more to learn about how to develop improved HOPS-directed treatments.

“And of course this also is an opportunity to do more basic research, now focusing on the human HOPS,” Stroupe said. “We don’t know nearly as much about human HOPS as yeast HOPS, so anything we learn will be a real step forwards, both in a purely curiosity-driven sense and as a way to devise even better HOPS-directed treatments.”

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