A preclinical mouse model that uses CRISPR reveals how prostate cancer spreads or metastasizes. The model developed by a team of researchers led by Weill Cornell Medicine demonstrates the routes prostate cancer metastatic cells take as they travel through the body, and could lead to more effective treatments.
Their findings are detailed in Cancer Discovery.
“The patterns by which primary tumors spread to metastatic sites remain poorly understood,” the researchers wrote. “Here, we define patterns of metastatic seeding in prostate cancer using a novel injection-based mouse model—EvoCaP (Evolution in Cancer of the Prostate), featuring aggressive metastatic cancer to bone, liver, lungs, and lymph nodes.”
“Using virtual maps, we can reveal the hidden highways of metastases, one day guiding us toward novel therapies that could act as roadblocks for cancer,” explained study senior author Dawid Nowak, PhD, assistant professor of pharmacology in medicine and the Walter B. Wriston Research Scholar in Medicine at Weill Cornell Medicine.
Approximately 12% of men receive a prostate cancer diagnosis in their lifetime. The American Cancer Society predicts about 35,250 deaths from the disease will occur in 2024 in the United States.
“Prostate cancer that spreads to the lungs, liver, and bones has the most impact on survival,” said lead study author Ryan Serio, PhD, a postdoctoral associate in medicine at Weill Cornell Medicine. When prostate cancer is confined to the primary tumor, survival is nearly 100%. When the cancer spreads, or metastasizes, the patient’s chance of survival drops to less than 40%.
A better understanding of prostate cancer metastasis opens possibilities for better treatments, said Nowak, who is also an assistant professor in the Tri-Institutional PhD Program in Computational Biology and Medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
In addition to Nowak and Serio, Christopher Barbieri, MD, PhD, associate professor of urology at Weill Cornell Medicine, and Adam Siepel, PhD, and Armin Scheben, PhD, computational biologists at Cold Spring Harbor Laboratory, contributed to the research.
The investigators injected 12-week-old mice with a virus designed to carry genetic information to the prostate. The virus contained instructions to delete two tumor suppressor genes, thereby encouraging the growth and spread of prostate cancer, and introduce a “barcode,” or a unique genetic marker that could then be edited with CRISPR technology.
Combined with tools such as genetic sequencing and bioluminescence imaging, this barcode allowed researchers to track the origins and movements of prostate cancer clones. They tracked the clones until the mice were up to 60 weeks old.
“With barcoding, we were able to follow clonal cells as they spread to different metastatic sites throughout the body,” Serio said. The researchers were able to pinpoint the clonal cells responsible for cancer spread and the patterns in which they spread. For example, they observed that while the primary tumor contained many prostate cancer cells, most metastases began with a small number of aggressive clones moving out of the tumor and into the bones, liver, lungs, and lymph nodes.
The researchers also observed that once most cancer cells spread to an organ, they were likely to stay there rather than spread to another area, with just a few closely related cells instigating additional spread. “These patterns of spread, or seeding topologies, in mice reflect what has also been observed in humans,” Serio said.
“We were very intrigued to find that the routes of metastasis from our models matched to some extent human cancer seeding so well,” Nowak said. “Using our techniques to map the metastatic cell trajectories gives us a great start in getting to the bottom of how this deadly cancer spreads.”
