March/April 2008

Understanding Metastasis

Pioneering biologist Robert Weinberg, the first to discover a gene that causes cancer, is now studying how the disease spreads.

By Katherine Bourzac, SM '04

Credit: Mark Ostow

Multimedia •  Green fluorescent protein labels are used to track cancer cells.

Cancer cells evade the immune system, travel down blood-vessel thoroughfares, colonize distant regions of the body, and recruit normal cells to support their cause. For all that, they aren't very clever, says Robert Weinberg, a professor of biology and member of the Whitehead Institute for Biomedical Research. They pull off complex biological feats using a few surprisingly simple tricks, which Weinberg's research is helping to reveal.

Weinberg has played a leading role in defining the battlegrounds in the war on cancer. He was the first to discover a cancer-­causing gene, and the first to isolate a human tumor-suppressing gene. And when it became clear that his successes had led to a baffling and increasingly complex picture of the disease, he came up with unifying, simplifying principles that helped move research in a promising new direction. Weinberg is now studying one of the most important and least understood processes in cancer: metastasis, the spread of malignant cells from an initial site to other parts of the body, where they cause secondary tumors.

"In the mid-1970s, we knew nothing about why cancer cells misbehaved," recalls Weinberg. But in 1982, he identified a cancer­-­causing mutation in a human gene called RAS. Before this discovery, the notion that cancer originated in mutated genes was speculative; in the years since, hundreds of mutations have been associated with cancer.

The discovery of RAS was followed by what Weinberg calls an "avalanche" of research tying cancer cells and tumor traits to a multiplicity of damaged genes. These findings have led to new therapies. But the sheer number of cancer-causing genetic mistakes that biologists have uncovered has overwhelmed them even as it has empowered them. The variety of the genes implicated raises a basic question about cancer: Is it actually a few hundred different diseases, each with its own genetic causes and disease processes? Or is it indeed one disease, with characteristics that are common to tumors in different patients and tissue types?

In 2000, Weinberg and Douglas Hanahan of the University of California, San Francisco, addressed this question in an article that has already become a classic. "The Hallmarks of Cancer," published in the journal Cell, argued that cancers should still be grouped together as one disease. Weinberg and Hanahan professed their faith in the possibility of simplifying cancer biology even in the face of a scientific literature "complex almost beyond measure." They predicted that the disease's complexity would be understood in terms of a few underlying principles, and they proposed six such "hallmarks"--acquired abilities that together make a successful tumor, be it in the breast, in the lung, or elsewhere. Cancer cells evade death, produce their own growth signals, resist antigrowth signals, continually encourage the construction of blood vessels, replicate on a potentially limitless scale, and can invade surrounding tissue to create distant tumors. The researchers suggested that this group of behaviors is characteristic of cancer--no matter what combination of genetic mistakes enables them, and no matter where in the body the cancer originates.

Weinberg and Hanahan are currently updating this work and may add one or two hallmarks, but Weinberg says the basic model has held up well over the past eight years. The global view it advocates--the concept of looking at groups of genes that cause common disease processes--is not just an interesting way of thinking about cancer. The work has been cited in hundreds of other papers. It has been put into practice in the emerging field of network or systems biology by researchers who have used it to make computer models that help them understand cancer cells and even predict individual patients' response to therapies.

As head of the Ludwig Center for Molecular Oncology, which was established at MIT in 2006 to foster metastasis research and is now part of the Koch Institute, Weinberg concentrates primarily on breast cancer. Most deaths from this disease are caused not by the original tumors in the breast but by secondary tumors that arise elsewhere in the body.