Researchers at Mount Sinai in New York are using advances in tissue preparation, imaging, image analysis and recording to investigate the biology underlying the known comorbidity between melanoma and Parkinson’s disease (PD). The project recently received a $100,000 pilot grant, co-funded by the Michael J. Fox Foundation, also in New York, and the Melanoma Research Alliance, Washington, DC.1
Having melanoma increases the risk of PD, and vice versa, said Deanna L. Benson, PhD. She is a professor of neuroscience at the Friedman Brain Institute and director of Microscopy and Advanced Bioimaging Core at the Icahn School of Medicine at Mount Sinai.
Epidemiological studies, mostly from the PD perspective, have repeatedly shown an increased risk in patients with PD of getting, getting, or having had melanoma, and vice versa.2-4 The link has been known for many years, Benson said. “And we realized that no one had really looked into it.” Benson is working with cancer researcher Jose Javier Bravo-Cordero, PhD, an associate professor of hematology and oncology at Mount Sinai in New York.
“We decided to work on this issue because we thought maybe together we could discover the biology underlying this shared risk.”
When they started their research, the researchers quickly realized that they could take advantage of the technical advances made in recent years to dynamically analyze tumor development. In particular, Benson explained, 2-photon microscopy allows researchers to image tumor cell behavior intravitally in mice as tumors grow. “You can label the vasculature, axons and tumor cells with fluorescent markers. Then you can dynamically observe the behavior of those elements and relationships to each other.”
Typically, Benson said, cancer researchers study tumor composition using different methods applied in several separate experiments. “We found that we lost data by conducting separate studies for each outcome, and that it would be much more beneficial to incorporate these new technologies to obtain multiple data sets from a single experiment.”
Since 2-photon microscopy cannot access the whole tumor, the project will also include a new rapid 3D cleanup protocol to visualize the whole tumor.5 “Lipids are removed from a solid tumor sample, so that you actually make the tumor transparent. Then you use a light sheet microscope to quickly image the entire tumor. The idea is that in a solid sample that has been cleared, we can examine and quantify relationships between each of these tumor-associated components, such as vasculature, tumor cells, and axons, and that data can be recorded and compared to the videos captured with using 2-photon microscopy.”
Another collaborator, StylianosKosmidis† PhD, an adjunct associate research scientist at the Mortimer B. Zucker Mind Brain Behavior Institute at Columbia University in New York, has developed a technique that can reverse the clearance process and standard cut and immunolabel the tumor tissue. These preparations, Benson said, can be viewed at very high magnification, which helps identify cell types and other characteristics that can then be registered in the other 2 data sets.
The aim of the project is to develop an imaging-based pipeline to maximize what researchers can learn from tumors at each stage of the analysis. “The idea is to capture data at different levels, from macro to micro, from the same samples.”
Researchers then use this pipeline to compare tumors growing in wild-type mice with tumors growing in mice that carry a knock-in of a mutation, specifically the G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene – which significantly increases PD risk in humans. “The one-point mutation is increasing LRRK2 kinase activity.”
At the time of going to press, researchers had begun to generate tumors in a mouse model. “We already have experience generating tumors in these mouse models and comparing tumor growth. We are currently troubleshooting the tissue clearance method this summer and should be ready to begin live imaging by early fall.”
Benson does not disclose any material financial interests.
1. Melanoma Research Alliance. Melanoma Research Alliance announces $13 million in grants to advance the prevention, detection, and treatment of melanoma.https://www.curemelanoma.org/assets/Uploads/MRA-Grant-Awards-2022.pdf. May 19, 2022. Accessed June 16, 2022.
2. Olsen JH, Friis S, Frederiksen K. Malignant melanoma and other cancers preceding Parkinson’s disease. Epidemiology† 2006;17(5):582-587. doi:10.1097/01.ede.0000229445.90471.5e
3. Ascherio A, Schwarzschild MA. The epidemiology of Parkinson’s disease: risk factors and prevention. lancet neurol† 2016;15(12):1257-1272. doi:10.1016/S1474-4422 (16) 30230-7
4. Dalvin LA, Damento GM, Yawn BP, Abbott BA, Hodge DO, Pulido JS. Parkinson’s disease and melanoma: confirmation and re-examination of an association. Mayo Clin Proc† 2017;92(7):1070-1079. doi:10.1016/j.mayocp.2017.03.014
5. Kosmidis S, Negrean A, Dranovsky A, Losonczy A, Kandel ER. A rapid, aqueous, reversible three-day tissue cleanup method for adult and embryonic mouse brains and the whole body. Cell Rep Methods† 2021;1(7):100090. doi:10.1016/j.crmeth.2021.100090
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