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A human breast cancer cell (green) lodged in a mouse lung capillary is surrounded by a red disruption of the vascular endothelial cells, caused by the cytokine angiopoietin-like 4, which, according to studies in Massagué's lab, is induced by TGF-beta. The weakened endothelium enables the seeding of pulmonary metastases.
“It was obvious, right off the bat, that [Massagué] had extraordinary talent,” says Czech. “He was a dream postdoc, someone who really went after the science, and who was dedicated to the sheer fun of discovery.” And unlike many postdocs, Massagué didn't have the distraction of wondering what he was going to do next, or how he was going to make a name for himself.
At the end of the two-year postdoc, Czech offered Massagué a non-tenure-track assistant professorship, with the option of spending 50 percent of his time on whatever he wanted, at the University of Massachusetts Medical School, where he had relocated his lab. It was an unusual offer. “We, in academia, don't usually retain people who've trained in our department,” says Czech. “It's an extraordinary breach of the way we operate. Joan was one of only two exceptions I can think of in 30 years.”
But the honor was lost on Massagué, who didn't really see the point. He was going back to Spain with his wife, Roser Salavert, whom he'd met in Barcelona and married shortly after starting his postdoc. Massagué asked what gain there would be in it, to which Czech, among other persuasives, answered that there'd be a few thousand extra dollars in his paycheck. “That I understood,” says Massagué. He had only one more question. What, he asked Czech, was tenure?
He took the offer and, with characteristic fearlessness, decided to try to identify the receptor for transforming growth factor beta—i.e. TGF beta. Growth factors are chemical telegrams that cells release into the space between one another. The growth factors then make their way to nearby cells, latch on to them via a receptor on the surface of the cell, and deliver their message. Only that's just the start, because the message actually needs to be passed to a number of different players before it's received and acted upon.
Little was understood about TGF beta, its receptor, the details of how its message got relayed, what the message said, and what happened as a result. It was so complicated, even people in the field kept their distance.
“I was told that it was very difficult, that I might fail,” says Massagué. “I said, 'I don't care, I'm going back to Spain. This is just to kill some extra time.'” He'd already done more than he'd set out to do in the United States. He had nothing left to prove to himself. “I thought I was already enough of a success,” he says. “Had I been a little more sophisticated and engaged in the career mode,” he says, “I would have been petrified to realize where I stood.”
Massagué told Czech he needed 100 percent of his time for TGF beta, obtained an independent investigator (R01) grant from the National Cancer Institute, and identified the receptor for TGF beta. In fact, somewhat to his dismay, he identified three of them, which meant triple the work figuring out what they all did. But his curiosity was piqued. He wanted to know what happened next. What chemical did that receptor make once TGF beta activated it? What gene did that chemical touch? What did the gene do as a result? Each answer only made him want to go further. “I didn't anticipate working on the entire pathway,” he says. But Massagué felt driven to know the whole story. Eventually, he says, the TGF-beta pathway became his “playground.”
Image: David Padua; Photo: Mark Mahaney