Can Tasmanian devils offer insights into battling human cancers? While we may not understand what the fictitious Looney Tunes cartoon character was trying to tell us, a recent study by scientists at Washington State University (WSU) and the Fred Hutchinson Cancer Research Center in Seattle, may translate into the animals’ potential survival and lead to eventual treatment for human cancers.
Their findings were recently published in the journal Genetics, in a paper titled “Spontaneous Tumor Regression in Tasmanian Devils Associated with RASL11A Activation.”
For over 20 years, devil facial tumor disease (DFTD) has wreaked havoc on the Tasmanian devil population, killing tens of thousands and threatening their survival in the wild. About the size of a small dog, Tasmanian devils are known for their nocturnal shriek and strong jaws. DFTD is a transmissible cancer spread by biting. Tasmania devils frequently bite each other in fights over mates and food. After the bite, a solid tumor then grows around the face or neck, with the power to break bones in the jaw—killing the animal after 6 to 24 months. But in the past few years, some devils have developed higher tolerance to infection and even resistance.
Determined to uncover the specific mechanisms underlying spontaneous tumor regression without treatment in human cancer patients, the researchers led by Andrew Storfer, PhD, professor of biological sciences at WSU, and Mark Margres, PhD, previously at WSU and now a postdoctoral fellow at Harvard University, delved into previous work focused on Tasmanian devil genetic variation association with the regression phenotype.
“Here, we used comparative and functional genomics to identify tumor genetic variation associated with tumor regression. We show that a single point mutation in the 5′ untranslated region of the putative tumor suppressor RASL11A significantly contributes to tumor regression,” wrote the researchers.
The researchers found a single genetic mutation leads to reduced growth of the transmissible cancer DFTD.
“This gene is implicated in human prostate and colon cancers,” said Storfer. “While the findings hold the most immediate promise to help save the world’s few remaining Tasmanian devils, these results could also someday translate to human health.”
The devil is in the details
To their amazement, the researchers found that the mutation contributing to tumor regression didn’t change the gene function, but instead turned on a gene that slows cell growth in the tumor when observed in the lab.
“RASL11A was expressed in regressed tumors but silenced in wild-type, non-regressed tumors, consistent with RASL11A downregulation in human cancers. Induced RASL11A expression significantly reduced tumor cell proliferation in vitro. The RAS pathway is frequently altered in human cancers, and RASL11A activation may provide a therapeutic treatment option for Tasmanian devils as well as a general mechanism for tumor inhibition,” the researchers explained.
About a third of all human cancers, including a high percentage of pancreatic, lung, and colorectal cancers, are driven by mutations in RAS genes.
The researchers used whole genome sequencing to identify a near-fixed genotypic difference between regressed and non-regressed tumors in a supposed regulatory region for the tumor suppressor gene RASL11A. Then they used transcriptomics to demonstrate that RASL11A was silenced in wild-type, non-regressed tumors but activated in regressed tumors, consistent with the genotypic data as well as RASL11A expression in human prostate and colon cancers. Lastly, they used cell proliferation assays to show that RASL11A activation significantly and negatively affected cancer cell proliferation in vitro in three of the four tumor cell lines investigated.
David Hockenbery, a cancer biologist at Fred Hutchinson Cancer Research Center, noted that current human cancer therapies focus on removing every trace of a tumor, often through toxic or debilitating treatments. “If there were ways that tumors could be tricked into regressing without having to administer cytotoxic drugs or deforming surgeries, it would be a major advance,” he added.
Their findings highlight RASL11A as a natural mechanism of tumor inhibition and a potential target in cancer therapy.
“Although this disease is largely fatal, we’re seeing tumors just disappear from an increasing number of individual animals,” Storfer noted. The researchers are hopeful in finding the effects of other promising mutations in regressed tumors as well.
“We hope to learn something that could be applied to understanding and possibly treating a number of human cancers in the future,” Storfer said.