Cancer metastasizes through the fusion of tumor cells with immune cells, according to a case report published online May 28 in Cancer Genetics.
“We think what is happening is the initial cancer cells from the primary tumor are blending or hybridizing with immune system cells that respond to the tumor as nonself. By hybridizing with those immune system cells, it looks like ‘self’ so that the immune system doesn’t attack and destroy [the tumor],” says first author Greggory LaBerge, a medical geneticist at the University of Colorado School of Medicine who also directs the Denver Police Department’s Forensics and Evidence Division.
LaBerge and his colleagues analyzed the DNA of a woman in her late 70s who had received a bone marrow transplant from an anonymous male donor several years earlier as treatment for her chronic myelomonocytic leukemia. She later developed metastatic melanoma. The tissue samples for this analysis came from the Department of Dermatology at the Yale School of Medicine, where the study’s lead author, John Pawelek, worked. (Pawalek, a longtime cancer researcher within the dermatology department at the Yale School of Medicine, died of an apparent heart attack on May 31. The Scientist will be running an obituary of him.) The authors used this sample to test a theory that immune cells and cancer cells fuse to lead to metastasis. Because the immune cells had the genome of the donor, while the cancer cells had the genome of the patient, it was possible to track the relative proportion of each at every stage in the metastatic journey.
The team’s hypothesis was that, if patient and donor cells were fused together at every point in metastasis, this would support the idea that the patient’s metastasis occurred due to such fusion. If only the patient’s DNA were evident at later steps of metastasis, then this would disprove the hypothesis that fusion fuels metastasis.
LaBerge and colleagues had several sources for their hypothesis, including a proposal from German physician Otto Aichel in 1911 that metastasis occurs when cancer cells and macrophages fuse. In more recent years, Pawelek showed that lab-created fusions of cancer and macrophage cells have a metastatic phenotype, and other scholars have shown a similar phenomenon in mice.
LaBerge and Pawalek’s team used a forensic genetic technique known as short tandem repeat analysis to track the relative proportion of patient to donor DNA in cancer tissue as the melanoma metastasized from the primary site to an axillary lymph node to her brain. The analysis uncovered a fusion of patient and donor cells from all samples—the primary tumor, the lymph node, and the brain. At the primary tumor site, the DNA derived from the patient was more prominent than the donor’s, in roughly a 10:1 ratio, meaning about 10 percent of cells were hybrids. But in the lymph node and brain the patient:donor ratio was roughly 1:1, indicating that all of the tumor cells were hybrids.
The authors argue that this work indicates that cancer-immune cell fusion is a major means of metastasis, and that treatments meant to inhibit such fusion across cancers could be more efficient than designing tailored treatments for different cancers.
“Tumors have tremendous plasticity in their ability to look like other cells, and to do things other cells can’t do,” says Mary Zutter, the director of the tumor-host interaction program at the Vanderbilt Ingram Cancer Center, who was not part of the study. Given this plasticity, Zutter has no doubt that the cancer-immune cell fusion demonstrated by the authors is one route of metastasis. She notes that this may especially be true for melanoma, pointing to the unique ability of melanoma cells to assume new forms. But Zutter disputes the idea that tumor-immune cell fusion leads to metastasis across cancer types, and notes that this is not a generally accepted idea.
Ashani Weeraratna, the chair of the biochemistry and molecular biology department at the Johns Hopkins Bloomberg School of Public Health, says that this paper offers definitive evidence for the idea that cancer-immune cell fusion is one cause of metastasis, but stops short of showing it is a common route. “In my experience, each cancer behaves so differently.”
For that reason, Weeraratna and Zutter are skeptical of the authors’ suggestion that preventing cell fusion might be a therapeutic approach to treating all cancers. Zutter says that targeting cancer-immune cell fusion would be a worthwhile goal but is unlikely to be a silver bullet.
LaBerge acknowledges the fact that the views proposed in the study are not mainstream, saying, “We are rebels, and John was a rebel.” Now that Pawelek has passed, LaBerge intends to continue the research efforts Pawelek championed.