Dr. Joan Massagué
During a 70-minute overview of the really nasty player in causing cancer deaths—metastasis,
or the spread of cancer from a primary tumor, which accounts for more than 90 percent
of cancer mortality—Dr. Joan Massagué
of Memorial Sloan-Kettering Cancer Center
occasionally sounded more like a cultural anthropologist than a cancer biologist. Foregoing
a pejorative tone about these cells, he described them as hearty and inventive tourists,
or rather émigrés that have a knack for wandering abroad and finding what they need to survive.
To be benign about something so malignant is to give up none of the warrior’s intent, however; Lipsett Amphitheater was filled to capacity not because Massagué tells agreeable stories, but because he is keen on learning how the sleeper cells of cancer terrorism survive and do their work. Figure that out, and you may have a chance against the disease, he suggested.
Currently program chairman in cancer biology and genetics at MSKCC and an HHMI investigator, Massagué called metastasis “the biggest problem in cancer biology.” In a talk describing “the signals and pathways of the metastatic niche,” he sought to explain what allows certain cells to “graduate” to the metastatic state.
Using the example of breast cancer in a woman, Massagué said that months before a tumor is detected and surgically removed, a process called dispersion and seeding may already have taken place. That is, micrometastases somehow found a window of escape and migrated throughout the body.
“Small does not mean inert,” he cautioned. “Most of these cells will perish, but some will get through.” Because they are traversing foreign territory, many of the cells run afoul of natural killer cells and other immune defenses. “These cells never saw that environment before, and perish.”
But a few establish beachheads, long before disease manifests. Latency can persist anywhere from months to decades. “We know the least about what we don’t see growing,” Massagué said.
He then set about literally deconstructing the lifestyles of these dangerous vagabonds, using two starting points, the source tumor and the site of successful colonization, the metastasis.
It was hard not to imagine the metaphors of travelogue or literary plot as Massagué set forth the conditions for metastasis: the vagrant cells must “survive on arrival,” demonstrating “early competence,” then “stay fit during early residence.”
An overflow crowd outside Lipsett Amphitheater listens to Massagué’s talk on Mar. 28.
Photos: Bill Branson
|Massagué set forth the conditions for metastasis: the vagrant cells must “survive on arrival,” demonstrating “early competence,” then “stay fit during early residence.”
In an example using lung adenocarcinoma, Massagué’s itinerant troublemakers stay put upon landing and “hug the vessel…they don’t let go, they don’t crawl. It takes time to colonize.”
Only a tiny minority of cells are capable of such high-risk tourism, “but that’s still too many,” Massagué said.
In their “interrogations” of the source tumor, Massagué and his colleagues found a number of signaling pathways that were linked to successful metastasis. The Wnt pathway, for example, is tied to metastasis to brain and bone.
Studying breast carcinoma that had spread to bone, his team learned that Src is clearly associated with that process.
Turning their analysis to metastases themselves, or end-products of the migratory cycle, Massagué and his colleagues again found a number of genes associated with secondary tumors, largely through gene expression profiling.
Two molecules emerged as especially bad actors. One, tenascin C hexabranchion, a six-armed critter “looks like it wants to play the piano,” quipped Massagué. But it has remarkable skill in initiating tumors in the lung when detected in breast tumors.
Another molecule, VCAM1, found in endothelial cells, also seems especially good at enhancing metastasis, especially “survival on arrival.”
Toward the end of his talk, part of the NCI Center for Cancer Research’s Eminent Lecture Series, Massagué demonstrated how some tumors “self-seed,” that is, send out colonists that not only thrive at a distant site but also report back and gain even more metastatic power, becoming “the best of the worst.” Such seeding can “go on in all directions, perhaps multiple times,” he said.
During a brief Q&A session, one weary attendee wondered how therapy could ever successfully thwart such relentless and sophisticated attack. Massagué, a warrior now, not a tour guide or anthropologist, said there are already countermeasures for some cancers, and that oncologists are getting better at stratifying patients based on tumor characteristics. The hunt for biological bin Ladens goes on.