In a new study published in Science Translational Medicine, Stage III human melanoma cells from 20 patients were implanted into specially selected mice with compromised immune systems. Using this xenograft model, in which tissue is transplanted from one species to another, the team observed reproducible differences in the rate at which the cancer spread in the mice, or metastasized, that correlated with clinical outcomes in patients.
Human melanomas that metastasized efficiently in the mice eventually progressed to advanced, Stage IV disease in patients – spreading to distant organs, such as the brain, liver, or lungs. When the melanoma did not metastasize efficiently in the mice, it also did not form distant metastases in patients.
This xenograft model will make it possible to study the mechanisms that regulate disease progression and distant metastasis of melanomas in patients. The researchers said they hope that their system will lead to new prognostic markers that identify patients at highest risk of disease progression as well as new therapies.
“We believe this is the only time in cancer biology that anyone has developed a xenograft model in which disease progression correlates with what happens in the patient,” says senior study author Sean Morrison, Ph.D., director of the Children’s Medical Center Research Institute at UT Southwestern and a Howard Hughes Medical Institute investigator.
“The highly immune-compromised state of the mice makes it possible to observe the metastasis of human melanomas, and to study intrinsic differences among melanomas in their metastatic potential,” he says
Previous studies of cancer metastasis were limited by a lack of workable models in which scientists could study the progression of a patient’s cancer cells in laboratory animals in a way that correlated with clinical outcomes, he says.
But such correlation was clear in this study by the research institute, an innovative collaboration that melds the leading clinical resources of Children’s Medical Center with the outstanding research resources of UT Southwestern. Melanomas that spread slowly and could not be detected in the blood of mice did not form distant tumors within 22 months in patients. Melanomas that spread rapidly in mice did form distant tumors in patients within the same time frame, giving rise to circulating melanoma cells in the blood of the mice. This finding suggests that entry of melanoma cells into the blood is a step that limits the rate of distant metastasis.
“Ultimately we want to identify new drug targets,” Morrison says. “There are promising ideas coming out of this work that we hope will lead to clinical trials in melanoma.”
The research arose from the Morrison laboratory’s innovative techniques for studying neural crest stem cells – work that was recognized in 2004, when Morrison was at U-M, with a Presidential Early Career Award for Scientists and Engineers. Neural crest stem cells make melanocytes, a type of cell that can mutate into melanoma if exposed, for example, to excessive sunlight.
This work originated with lead author Elsa Quintana and Mark Shackleton in Morrison’s former lab at the University of Michigan. Other key collaborators from the University of Michigan were Douglas R. Fullen, director of dermatopathology, and Timothy Johnson, director of the Multidisciplinary Melanoma Clinic. Other UTSW researchers involved in the study were Elena Piskounova and Ugur Eskiocak, both postdoctoral researchers in the Children’s Research Institute.
“This animal model offers unprecedented opportunities for discovery efforts that could be translated into patient care,” Johnson says. “Dr. Morrison and I share a core mission to effectively treat melanoma, and that shared belief is the basis of the past, present and future collaboration between UT Southwestern and the University of Michigan.”
Research support came from the Howard Hughes Medical Institute, the Melanoma Research Foundation, the Allen H. Blondy Research Fellowship at the University of Michigan, and the Cancer Prevention and Research Institute of Texas.
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