Zebrafish models could help develop precision cancer therapies
HSCI scientist Leonard Zon, M.D. uses zebrafish as a model to study different cancers. Now, he has used this approach to reveal how mutations in a gene called SPRED1 are involved in mucosal melanomas — rare tumors that grow in the linings of the respiratory, digestive, and genitourinary tracts.
Mucosal melanomas do not typically carry the same the genetic mutations associated with better-studied skin melanomas, and the biology behind them is not well understood. Published in the journal Science, the new study links SPRED1 with cancer for the first time and shows the detailed mechanism of how SPRED1 contributes to tumor development in zebrafish.
What they did
To discover the genetic drivers of mucosal melanoma, Zon and his colleagues at Boston Children’s Hospital and University of California, San Francisco started by analyzing genetic data from patient tumors. When they found mutations in the gene SPRED1, they created zebrafish models to figure out exactly how those mutations resulted in mucosal melanoma.
What they found
As described in more detail here, when the researchers inactivated SPRED1, melanoma cells grew faster. The reverse was also true, showing that SPRED1 normally acts as a tumor suppressor, inhibiting or regulating growth.
The research team also studied the relationship between SPRED1 and genes that have been previously associated with mucosal melanomas, including KIT. They found that when SPRED1 was lost, mucosal melanoma tumors became resistant to a compound that inhibits KIT. This suggested that patients who are missing the SPRED1 gene would not benefit from existing KIT-inhibiting drugs.
The next step is to test whether patients with SPRED1 mutations would benefit from drugs that inhibit a different part of the cellular pathway than KIT, such as MEK inhibitors.
Zon’s lab also plans to look for SPRED1 mutations in other kinds of tumors, because the mutations might be an important predictor of how patients will respond to particular drugs. Currently, SPRED1 is not part of the panel of cancer-related genes often used to test patients, notes Julien Ablain, Ph.D., co-first author of the study.
“For targeted therapies, you really need to understand the molecular mechanism,” he says. “That is the first thing this paper is going to change.”
Why it matters
Patients with cancer respond differently to different drugs, so predicting drug response can help identify the best treatment approach.
“This paper establishes the zebrafish as an extremely quick model to study the many genes mutated and regulated in human cancer,” says Zon, who is director of the Stem Cell Research Program at BCH, Harvard professor of stem cell and regenerative biology, and Executive Committee Chair of the Harvard Stem Cell Institute.
“In the future, patients could have their specific mutations modeled in zebrafish to guide decisions about their treatment.”
Ablain J. and Xu M. et al. (2018). Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma. Science. DOI: 10.1126/science.aau6509
Boston Children’s Hospital Vector blog. (2018). Fishing for new leads in rare mucosal melanoma.