How cancer spreads

Since early in his career, John Pawelek, a senior research scientist at the Yale School of Medicine, has studied melanoma cells. Now, thanks to an unlikely series of eureka moments, his specialized dermatologic research has led to sweeping insights about the nature of malignancy itself. Pawelek and dermatology department colleague Ashok Chakraborty have demonstrated the workings of the mechanism behind metastasis, the deadly process by which cancer cells spread to sites all over the body.

Pawelek's research detour began in the early 1990s, when a couple of paragraphs in a melanoma journal article by three Czech scientists caught his eye. "The article asked the theoretical question, 'Is melanoma metastasis the result of cancer cells fusing with white blood cells?'" he says. A largely overlooked cell fusion theory of metastasis was actually first proposed in 1911 by German pathologist Otto Aichel, but the Czech idea was "an epiphany for me"—because white blood cells are capable of migrating throughout the body.

Around the same time, Pawelek's son gave him a book by evolutionary biology doyenne Lynn Margulis, who believes that the cells in our bodies are hybrids of prototype human cells and ancient bacteria. Pawelek was immediately struck by the fact that both Margulis and the journal article he'd just read were proposing the union of different cell types. "I said to myself, 'They're saying the same thing.'"

He contacted Margulis, who encouraged him to test the white blood cell hypothesis post-haste. "She was so excited about it that she called me at 7:30 on a Sunday morning, even though she didn't really know who I was," he recalls.

Over the following decade, Pawelek began to explore the fusion theory in the lab by creating an experimental strain of white blood cells combined with tumor cells. When he and his colleagues implanted these hybrid cells into mice, most of the mice quickly acquired metastatic cancer and died. The team analyzed the molecules used in the artificial hybrid cells to kick-start the metastasis process. To their surprise, these molecules were strikingly similar to those produced by naturally occurring human metastatic cells.

Findings like these, repeated in several investigations over time and published in the May issue of Nature Reviews Cancer, confirm that the fusion theory has passed its first tests with flying colors.

"I think this theory will account for the bulk of metastasis," Pawelek says. "It will provide a new way of looking at cancer therapy, because now we have a whole different cancer mechanism to think about." He plans future studies at bone-marrow transplant centers to document exactly how white blood cells produced in human bone marrow fuse with the nuclei of cancer cells.