leukemia

Shifting melanomas play hide and seek

U. MICHIGAN (US) — Melanoma tumor cells are able to switch various genes on and off, in a stealthy, shape-shifting attempt to avoid researchers seeking new treatments.

A new study, which also finds that most types of melanoma cells can form malignant tumors, refutes the model that claims a handful of rare stem cells drive the formation of malignant tumors and the best way to treat the disease is by targeting them, rather than trying to eliminate all the cells at once.

“Some have suggested that melanoma follows a cancer stem cell model in which only rare cells are able to proliferate extensively and form new tumors,” says Sean Morrison, director of the Center for Stem Cell Biology at the University of Michigan.

Morrison analyzed 44 sub-populations of human melanoma cells, and all 44 had a similar ability to form tumors when transplanted into mice.

“Our results suggest that most melanoma cells are capable of driving disease progression and that it won’t be possible to cure patients by targeting rare sub-populations of cells,” Morrison says. “We think you need to kill all the cells.”

The findings are published Nov. 16 in the journal Cancer Cell.

The study is the first to show that tumor-forming melanoma cells have “phenotypic plasticity”—that is they can flip a genetic switch changing the types of proteins expressed on the cells’ surface. Patterns of surface proteins are used to identify different cell types and are commonly called cell surface markers.

“The fact that these markers are turned on and off by melanoma cells raises the possibility that melanoma cells may also turn on and off genes that regulate clinically important characteristics like drug resistance and metastatic ability,” Morrison says.

“The ability to transition between various states may make melanoma more difficult to treat.”

While their results argue against a cancer stem cell model for melanoma, they don’t invalidate it, particularly for certain leukemias and other cancers.

“It will be critical to determine which cancers follow a stem cell model and which do not, so therapies designed to target rare sub-populations of cells are not inappropriately tested in patients whose disease is driven by many diverse cancer cells,” says Elsa Quintana, one of the paper’s first authors.

The model assumes that cells differing in marker expression also differ in function, and that only a very small subset of cancer cells displaying the critical marker pattern—less than 1 percent of cancer cells—can form tumors.

Most of the cancer cells that compose tumors have little or no capacity to proliferate or to contribute to disease progression, according to the model.

“The cancer stem cell model says that tumor cells are organized hierarchically, and that only the cells at the top of the hierarchy form tumors. Cells at the bottom of the hierarchy can’t,” Morrison says, but his team was unable to find any subset of melanoma cells that lacked the ability to form tumors.

“In our model, all these cells can form tumors. And they’re phenotypically different from each other not because they’re hierarchically organized but because they’re just turning these surface markers on and off.”

All tumor-forming melanoma cells gave rise to progeny with a variety of marker patterns, and all of those sub-populations retained the ability to form tumors. The marker changes appeared to be reversible, rather than being associated with a transition from tumor-forming to non-tumor-forming states.

Melanoma kills more than 8,000 Americans each year.

“These new findings significantly advance our understanding of melanoma,” says Timothy Johnson, director of University of Michigan’s melanoma program and a co-author of the paper.

“This type of groundbreaking discovery achieves our core objective of combining clinical studies with laboratory research to develop new and better treatments for optimal patient care.”

The work was supported by the Howard Hughes Medical Institute and the Allen H. Blondy Research Fellowship.

More news from University of Michigan: www.ns.umich.edu/

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