If tumors didn’t spread — metastasize — cancer would be far less lethal than it is, says MIT’s Robert Weinberg. “Metastasis is responsible for about 90 percent of cancer deaths,” notes Weinberg, the Daniel K. Ludwig and American Cancer Society Professor of Biology.
But metastasis isn’t just dangerous, it’s also cancer’s black box. Doctors know where cancers spread — for example, breast cancer, one of Weinberg’s special interests, goes to bone and the brain. But not much has been known about how they spread.
“Just a few years ago,” says the faculty member, “there were many opinions about how metastasis occurs and little evidence to support any of them. But now, we’ve begun to see the outlines of how cells escape the primary tumor and travel to new sites in the body.”
Weinberg, with others at MIT, has helped create that progress. Among his contributions: helping show how tumors hijack the machinery of human embryonic development in order to spread.
But much is still murky, including how tumor cells from one part of the body can flourish in an entirely new setting — a biological feat seemingly as implausible as fish thriving in a cornfield.
Now, though, MIT has an exciting new platform for probing the mysteries of metastasis: the Ludwig Center for Molecular Oncology, which was created thanks to a gift from the Virginia and D. K. Ludwig Fund.
The launch of the center — part of the MIT Center for Cancer Research — is very timely, says Weinberg, the new enterprise’s first director. “We now have many of the biochemical tools needed to make rapid inroads on metastasis,” he notes. And while this doesn’t mean new anti-metastasis drugs are imminent, he believes such agents will emerge in time.
“People like me,” he says, “work with the faith that if we can understand the mechanisms of cancer, this will ultimately lead to new means of treating it.”
FOCUSING ON TODAY
Weinberg, also a member of the Whitehead Institute for Biomedical Research, got into metastasis studies the way he’s gotten into many areas of cancer biology: by happening on the issue while probing other topics.
This unplanned style, he says, may reflect his upbringing. His parents fled Nazi Germany. “They lost almost everything,” says the Pittsburgh native, “so I grew up in a household where the psychology was, ‘be grateful for what you have today and don’t focus too much on tomorrow.’:
Whatever its source, Weinberg’s approach has been strikingly successful. In the early ‘80s the scientist was the first to identify an oncogene — a cancer-linked gene — from a human tumor. He and his co-workers also found the first human tumor suppressor gene. Other key discoveries followed.
Weinberg’s exploits have won him fistfuls of honors, including the Sloan Prize of the General Motors Foundation and the National Medal of Science. He’s also seen his work translated into treatments. His group’s discovery of the Her2-neu gene opened the way for the drug Herceptin, which has prolonged the lives of many with advanced breast cancer.
The group’s move into metastasis work occurred after the researchers had created the first human tumor cells capable of growing outside the body. “The cells,” notes Weinberg, “formed fast-growing tumors when injected into mice, but these tumors failed to spread. So then the question was, what else has to happen for cancer cells to migrate to distant points in the body?”
One thing was clear: metastasis is driven by genes that operate differently from those that instigate the original tumor. But what were those genes? When the researchers infused the tumor cells with a gene known to be active in human embryos, the group got at least part of the answer: this gene, normally turned on only in embryos, somehow comes back to life in certain cancers, causing them to spread.
That and other advances have bolstered the theory that a handful of genes trigger most major steps in metastasis, from the transformation of certain cells in a tumor into a “travel-ready” guise through arrival of such cells at new bodily locations.
For Weinberg, the role of these genes (seven are known so far) was a stunning turn in the metastasis story. “I never imagined that just a few transcription factors — that is, proteins which turn on target genes — could choreograph most of the steps in metastasis,” he says.
Pinpointing these genes raises intriguing possibilities, from using them to predict just how dangerous a specific tumor will become to disrupting the actual steps by which tumors spread.
Weinberg says some early signs are promising. One of the metastasis-promoting genes, for example, may be a warning sign for certain breast tumors. “It seems very useful in diagnosing a subset of a particularly virulent form of that cancer,” he notes.
As for a role in treatment, Weinberg believes that while such an outcome is likely, the timing’s unpredictable. “Much of the progress in treating cancer over the past 30 years has come from basic, preclinical research,” he notes, “and I believe that if we and others like us do our jobs well, we’ll see that happen again with metastasis.”