Against Metastasis: Brunhilde Felding-Habermann Works to Strip Away the Secrets of Cancer’s Dangerous Advance

The deadliest twist in a tumor’s evolution goes by the dread word metastasis. It is what happens when cells, like seeds, detach from a primary tumor, escape to the byways of the circulatory system, and grow into new tumors in distant, often vital organs—the liver, the lungs, bone, and brain. Most cancers would be far less lethal if they stayed local and did not metastasize. “Metastasis is the major cause of death in cancer patients,” said Brunhilde “Brunie” Felding-Habermann, associate professor in The Scripps Research Institute Department of Molecular and Experimental Medicine.

Metastasis is also one of the most elusive problems of cancer biology. What causes a primary tumor cell to detach and go metastatic? How does it survive the rushing violence of the bloodstream and grab a vessel wall? How does it migrate from a vessel to a nearby organ and thrive in this new milieu? Few scientists have done as much to answer such questions as Felding-Habermann.

She grew up in Germany, and obtained her biochemistry PhD from the Philipps University of Marburg (established in 1527). In her doctoral work and later in a fellowship at the Fred Hutchinson Cancer Research Center in Seattle, she studied glycolipids—complicated sugar-fat molecules found in the walls of cells—and helped establish that they have cancer-related variants that can ease a wandering melanoma cell’s path by defusing local immune responses. She moved to Scripps Research to do postdoctoral research in 1993, and by then had turned her attention to the protein enablers of metastasis.

Only a tiny fraction of cast-away primary tumor cells survive their journeys through the circulatory system, where they are pounded by other cells, snapped at by macrophages, and hustled along at the human-scale equivalent of more than 1,000 miles per hour. Felding-Habermann, working in the Scripps Research lab of molecular pathologist David Cheresh (now at the University of California, San Diego), identified a crucial factor that helps them achieve this feat: a surface protein known as an integrin. Found on many cell types, integrins are grappling-hook-like adhesion molecules that fasten cells to their local environment. They can exist in an inactive, folded-away state, to make it easier for their host cells—such as naturally circulating immune cells—to migrate. But under certain circumstances, they can be triggered into an active, grappling state. Felding-Habermann found that successful metastatic tumor cells get around by using their integrins in a similar manner. “By looking at the activation state of a tumor cell’s integrins, we found that we could judge how aggressive the tumor cell is,” she said.

By then it was clear that integrins play supporting roles in primary tumors as well by promoting new blood vessel growth and thwarting apoptosis, and the lab began to investigate ways of blocking them. Merck KGaA (the German chemical and pharma company, a cousin to the US-based Merck & Co.), soon took an interest, licensing the technology and hiring Felding-Habermann. She spent the next two and a half years back in Germany, devising assays to screen for drug compounds that could block the adhesion and migration-enabling integrins on tumor cells.

She returned to Scripps Research as a faculty member in 1998, and although she preferred the academic environment, her work now was more therapy-oriented than ever. In one line of investigation, she collaborated with Scripps Research chemist Kim Janda, who had developed libraries of B-cell antibody-coding genes from advanced breast cancer patients. “We screened that library, with the idea of finding antibodies that recognize a metastatic tumor cell,” she remembered As she, Janda, and their colleagues reported in the Proceedings of the National Academy of Sciences in 2004, the most metastasis-specific antibody turned out to be one that targeted the activated form of an integrin known as integrin alpha v beta 3. In fact, the antibody precisely mimicked a key amino acid sequence on the integrin’s natural binding site (found, for example, on fibronectin, an extracellular matrix glycoprotein). In a mouse model, the antibody inhibited breast cancer metastasis to the lung and reduced existing metastases.

Felding-Habermann’s lab is now working with the lab of Scripps Research chemist Peter Schultz to conjugate these antibodies to a cytotoxic compound called auristatin, so that they don’t just bind to integrin-bearing tumor cells—but very effectively wipe them out. “Schultz’s lab has devised an advanced method of conjugating antibodies with these cytotoxic molecules that makes it virtually impossible for the drug molecule to inadvertently fall off and get to a site where it’s not supposed to go,” she said.

Platelets and Metabolism

Another active line of research in the Felding-Habermann lab concerns platelets, the sticky mini-cells that circulate in the blood and help patch wounds. Scientists have long noted the links between cancer and excessive blood clotting—a frequent killer of advanced metastatic cancer patients—and it turns out that platelets are a major explanation for the link. They bind to circulating tumor cells, cloaking them from surrounding immune cells and enhancing their stickiness, making it easier for them to grab vessel walls and pull themselves out of the torrent. “But platelets in this context are not just like pieces of velcro,” said Felding-Habermann. “They’re loaded with granules containing growth factors, cytokines, and other bioactive compounds, and we now think that these provide signals that boost the ability of tumor cells to leave the bloodstream and colonize a nearby organ.” Investigating the metastasis-boosting pathways of platelets, and looking for ways to block them, is now a major activity in Felding-Habermann’s lab—and a broad new area in cancer research generally.

A third and highly promising—but so far relatively unpublicized—line of research in the Felding-Habermann lab aims to increase understanding of the metabolic changes that help a tumor cell metastasize successfully. In work reported in 2007, Felding-Habermann and her colleagues found that brain-metastatic breast cancer cells underwent changes in protein expression suggestive of a significant metabolic shift—one which ramps up various forms of energy production and at the same time helps protect the cells from the damaging free-radical byproducts of oxygen-intensive metabolism. Her lab is following up on these findings. “The aggressiveness of tumor cells turns out to be closely linked to malfunctions in mitochondrial energy pathways,” she said. “We think there is now an excellent opportunity to normalize tumor cell metabolism, and thereby interfere with tumor progression.”

Despite running a busy lab, Felding-Habermann finds time for volunteer work in support of the National Breast Cancer Coalition, teaching classes in basic lab work and cancer biology to visiting teams of cancer patient advocates. “Academia is great because you can follow a question just out of curiosity, but these groups really bring home the message that we need to do research to improve cancer patients’ quality of life and their chances of overcoming the disease,” she said.

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