Cancer Biology, Cell Biology
Dana-Farber Cancer Institute
Dr. Pellman is Margaret M. Dyson Professor of Pediatric Oncology at the Dana-Farber Cancer Institute and at Children's Hospital Boston. He is also a professor of cell biology at Harvard Medical School.
Aneuploidy, Polyploidy, and Cancer
If you hang around cancer researchers, you're going to hear the word "target" frequently. A target is a cancer telltale, a thing supposed to be so particular and so specific to cancer cells—yet not to normal cells—that researchers can program its GPS coordinates into a drug rocket and fire away. That's the theory. The reality is that cancer cells try not to go around with targets painted on their cellular backs.
The search for novel cancer targets goes on, but sometimes a researcher will double-back, hauling some half-forgotten bull's-eye out of the scientific attic for reexamination. David Pellman, a pediatric oncologist and cancer biologist at the Dana-Farber Cancer Institute and Children's Hospital Boston, dragged out one of the oldest targets for a new look.
In 1914 the German biologist Theodor Boveri first proposed that tumors develop because they have abnormal numbers of chromosomes, known as aneuploidy. Aneuploidy can develop by a "bottom-up" mechanism, where cells gain or lose chromosomes over the course of many divisions. Boveri also recognized that aneuploidy could develop by a "top-down" path. If cells fail key steps in cell division, they can become polyploid, that is, they have two, four, and more copies of the basic human diploid chromosome set, which is itself a merger of two half-sets, one each from the parents. Boveri theorized that polyploidy—the doubling and redoubling of chromosome sets—could cause ordinary cells to run off the rails, setting them on the road to becoming endlessly dividing aneuploid cancer cells.
Boveri's pioneering work made him a founding father of several fields, including cell biology and cancer biology. But the idea that polyploidy itself could trigger cancer was never put to a direct test, according to Pellman. As cancer biologists from Boveri onward learned, there is a lot going on in cancer cells besides polyploidy.
The experimental technology and basic knowledge needed to unravel the old "cause or effect" conundrum just wasn't there in Boveri's day, says Pellman. "But the idea that the doubling of the genome would contribute to tumor development is one of those ideas that's been out there, would get revisited every ten years or so, but would then be forgotten." This time around, it was Pellman who came calling. He came bearing yeast and mice, or more properly, he brought animal model systems useful for identifying genes active only in polyploid cells and for testing the impact that polyploidy has on genomic stability.
Whatever it does in human cells, polyploidy is common and not cancer-provoking in many organisms, including certain kinds of salmon, wheat, strawberries, and yeast. Pellman used his yeast-screening system to separate the genes active in diploid and haploid yeast from those active only in polyploid yeast. He winnowed that list down to a handful of genes whose presence was life-or-death in polyploid yeast. Knock out any of those genes and polyploid yeast die. Pellman now had a shorter roster of genes that exhibited "ploidy-specific lethality" and that gave him a marker for polyploid cells.
To test the relationship between polyploidy and cancer, Pellman turned to a mouse model, isolating primary epithelial cells in which p53—the control gene that normally halts cells with extra chromosomes (a state called aneuploidy in mammals) from proceeding—was knocked out. With the p53 "brakes" off, Pellman then developed procedures to separate genetically identical diploid and tetraploid cells. When exposed to a carcinogen in vitro, only the tetraploid cells turned malignant. Without carcinogen exposure, only the tetraploid cells implanted in immune-suppressed "nude" mice rolled down the carcinoma development path. Polyploidy alone had made the cells genomically unstable.
Looking more closely at the cellular machinery, Pellman could see simple mechanical reasons. All those extra chromosomes, centromeres, and mitotic spindles in the tetraploid cells were getting in each other's way. Although the ratios of these cellular parts remained unchanged, after scaling up, the parts no longer fit together properly. The work now had implications well beyond vindicating Boveri.
Pellman comes from a class of medical students who were bitten by the basic research bug early and never recovered. He went to medical school at the University of Chicago and at the same time studied cancer genes in Hidesaburo Hanafusa's laboratory at the Rockefeller University. He then moved to Boston where he shuffled from a clinical residency at Children's Hospital to a research fellowship doing cell division and yeast genetics research in Gerald Fink's lab at the Whitehead Institute for Biomedical Research. That post was followed by an oncology fellowship back at Children's and the Dana-Farber Cancer Institute, which was followed by another stint with the yeast in Fink's lab. Pellman enjoyed both worlds but was continually drawn to the lab because of the frustrating lack of effective treatments in the clinic.
Pellman kept on with the yeast. He took a joint faculty appointment at Children's and Dana-Farber, pursuing a dual career as clinician–basic researcher until his yeast studies finally won out. The success of his lab, new appointments at Harvard Medical School, publication of high-interest papers, and now being named an HHMI investigator, all have carried Pellman into full-time lab research.
He says that the HHMI investigator appointment will allow him to branch out further, looking into the evolutionary implications of polyploidy and digging deeper into the mechanics of chromosome duplication in the crowded polyploid world. But Pellman knows exactly where he wants to go with his ploidy-specific lethality genes. If he can extend the work into homologous human genes, Pellman says he'll have a direct handle on how aneuploidy alters the basic biology of the cell, an understanding that might lead to new therapies.