Escape artists
Without a restraining system for individual cells, living things would literally fall apart. A constant conversation between cells and their surroundings—carried on through a complex sequence of protein signals—assures that cells generally stay locked in place.
Vicki Boussiotis, MD, PhD, (left) and Maria Esther Lafuente PhD, are exploring how metastatic cells become "unstuck" from surrounding tissue.
In metastatic cells, however, this adhesion mechanism fails. With a suppleness that would impress Houdini, tumor cells that escape their confines can make their way through tissue that would be impassable to most cells.
DFCI's Vicki Boussiotis, MD, PhD, is studying one of the key actors in cell adhesion and migration, a protein called Rap1. When activated, Rap1 travels from the interior of the cell to the outer membrane, where it helps pin the cell to the extracellular matrix.
But what initiates this journey? Boussiotis and her colleagues discovered a gene called RIAM that prompts Rap1's movements. "When we activated the gene in leukemia cells, the cells had a high degree of adhesion," she reports. "When we 'knocked out,' or shut down, RIAM, the cells weren't able to adhere." Without RIAM to send it on its way, Rap1 stays deep within the cell, preventing it from anchoring.
"Making a link between the expression of these genes and the aggressiveness of tumors could lead to new diagnostic tests for metastatic disease."
— Vicki Boussiotis, MD, PhD
Nor is RIAM the only gene able to accomplish this. After cloning RIAM — copying it thousands of times over for study — Boussiotis and her team found an entire family of genes to which it belongs. When researchers at the Massachusetts Institute of Technology cloned another member of this family, they found that, like RIAM, it operates near the cell membrane and helps the cell hold its shape. It also has a role in cell mobility, but apparently the reverse of RIAM's: when the MIT team knocked out the gene, cells became less mobile. If the gene didn't work in the microscopic worm C. elegans, the creature was unable to move, and died.
"Making a link between the expression of these genes and the aggressiveness of tumors could lead to new diagnostic tests for metastatic disease," Boussiotis predicts. "Beyond that, there is the possibility of developing gene therapy techniques to compensate for abnormalities in RIAM and its cousins."
Gaining momentum
Just like the rest of cancer science, research into metastasis is funded by a combination of government, private, and foundation sources. And as with medicine in general, discoveries about the basic biology of metastasis are opening new possibilities for therapy: knowing which genes are responsible for cancer's spread is the first step toward better treatments. That is the premise, and promise, of Dana-Farber investigators' efforts in this field.
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