Following the pathways to metastatic melanoma

By Clint Talbott

Molecule by molecule, Natalie Ahn strives to understand how melanoma, the most dangerous kind of skin cancer, develops and spreads. She does so in part by studying the metabolic pathways implicated in cancer and “weighing” proteins and peptides, research that has yielded new insight into how cancers metastasize—or spread throughout the body.

This work is one reason Ahn, professor of chemistry and biochemistry at the University of Colorado Boulder, has been named a 2012 College Professor of Distinction by the College of Arts and Sciences. She is also an investigator of the Howard Hughes Medical Institute, director of the Predoctoral Training Program in Signaling and Cellular Regulation and associate director of the BioFrontiers Institute.

She and fellow 2012 Professor of Distinction Keith Maskus publicly outlined their work during public presentations this fall. (See related story on Maskus.)

Ahn’s research investigates enzymatic and cellular mechanisms underlying cell signaling. She uses technologies in functional proteomics and hydrogen-deuterium exchange mass spectrometry for her research in signal transduction.

Cancer is characterized by unregulated proliferation of cells. Melanoma is cancer of pigment cells in skin and eyes.

About 160,000 new cases of melanoma appear annually worldwide; about 50,000 people die from the disease each year.

The disease is easy to spot and remove when it appears on the skin as a “primary” melanoma. When melanoma becomes metastatic, it becomes extremely deadly.

“For reasons that are not clear, still, stage 4 metastatic melanoma is very hard to treat,” Ahn said. “For some reason, it’s very resistant to conventional chemotherapies that are very successful with other cancers.”

Patients with stage 4 metastatic melanoma typically die within six to 12 months.

“So we are very interested in understanding what is underlying this disease.”

What underlies most cancers is signal transduction pathways. These are mechanisms that allow cells to sense molecules in their environment.

Signals on the outside of a cell include growth factors or hormones. A protein inside the cell, called a receptor, senses the signals. This triggers a series of events that leads to the transfer of information from one molecule to another molecule, “sort of like a bucket brigade,” Ahn said.

These signal-transferring molecules create a response, often a change in gene expression, that lead to changes in cell responses—like enhanced cell proliferation or cell movement.

In cancer, these signaling pathways can go awry. Melanoma is linked with mutations in the genome of pigment cells. In such cases, the pathway can be turned on even in the absence of an actual signal. That leads to cell proliferation and many hallmarks of cancer, including metastasis.

“So you can see why developing inhibitors that target enzymes in this pathway might provide important therapeutics for melanoma,” Ahn said.

One melanoma treatment that inhibits the activity of a mutant form of an enzyme has already been approved by the FDA. Whereas only about 10 percent of melanoma patients responded to conventional chemotherapy, and those who do respond do so “fairly poorly,” this targeted drug was effective in 85 percent of patients who had that genetic mutation.

Only those patients whose genes had the mutation were eligible for treatment. “Within weeks, you could see the tumors melt away, and so this was an enormous success for what is referred to as personalized medicine,” the use of scientists’ understanding of signal transduction pathways to develop better, targeted treatments for cancer.

“But it’s actually not a cure, because it turns out that in patients treated with this drug, almost everyone relapses, and almost all patients who were present in the initial clinical trials have now died.”

The median enhanced survival time is only about seven months, and much remains to be learned, Ahn said.

Among the unanswered questions are what changes when the drug is administered to turn the pathway off and what new targets might exist for development of better therapeutics.

Ahn and her fellow researchers pursue this line of inquiry partly by determining the mass of molecules—or “weighing” them with mass spectrometry. Those efforts have revealed, for instance, that the protein FAM129B is a target for signals from the mutated protein targeted by the drug Ahn mentioned. FAM129B is implicated in “cell invasion,” which is associated with metastasis.

Another discovery is of mechanism that links the ability of cells to distinguish their front from back, referred to as “cell polarity”, to their ability to invade.  This is controlled by another molecule in the cancer environment called Wnt5a, which is produced by the melanoma cells and upregulated in aggressive cancers.  Understanding this mechanism, might lead to new targets for therapeutics that control metastasis.

Ahn came to CU-Boulder in 1992 after completing her Ph.D. and postdoctoral work at the University of California, Berkeley, and the University of Washington, respectively.

As she acknowledged being named a professor of distinction, Ahn said, “I have a lot of people to thank.” She mentioned that “working with students is the best thing about being a professor.”

Ahn also thanked her colleagues. “One of the best things about being at CU-Boulder is that this is a place where the collegiality and cooperation between faculty are far better than any of the many universities I’ve visited.”