New CRISPR model offers deeper insight into prostate cancer metastasis

A new preclinical model using CRISPR, an advanced technology that allows scientists to cut and edit genes, has given Weill Cornell Medicine researchers and their colleagues a deeper insight into how prostate cancer spreads or metastasizes.

In the study, published Sept. 23 in Cancer Discovery, scientists charted the complicated routes prostate cancer metastatic cells take as they travel through the body.

"Using virtual maps, we can reveal the hidden highways of metastases, one day guiding us towards novel therapies that could act as roadblocks for cancer," said study senior author Dr. Dawid Nowak, assistant professor of pharmacology in medicine and the Walter B. Wriston Research Scholar in Medicine at Weill Cornell Medicine.

The impact of prostate cancer metastases

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 Dr. Ryan Serio, 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 Dr. 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.

An innovative model

To study the development and spread of prostate cancer, the research team developed a new mouse model called EvoCaP. In addition to Drs. Nowak and Serio, Dr. Christopher Barbieri, associate professor of urology at Weill Cornell Medicine, and Drs. Adam Siepel and Armin Scheben, computational biologists at Cold Spring Harbor Laboratory, contributed to the project.

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-;cells that arise from the original cancer cell that share the same genetic mutations and that grow, multiply and spread. 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."

Dr. Ryan Serio, postdoctoral associate in medicine, Weill Cornell Medicine

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.

They 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", Dr. 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," Dr. 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."