Innovative model provides valuable insights

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

Inside to workPublished on September 23 Cancer Discovery, Scientists have mapped the complex routes that prostate cancer metastatic cells follow as they travel through the body.

“Using virtual maps, we can uncover the hidden highways of metastases, which could one day lead us to new treatments that could prevent cancer,” said the study’s senior author. Dr. David Nowakassistant professor of pharmacology in medicine and the Walter B. Wriston Research Fellow in Medicine at Weill Cornell Medical College.

Impact of Prostate Cancer Metastases

Approximately 12% of men will be diagnosed with prostate cancer during their lifetime. The American Cancer Society predicts that there will be approximately 35,250 deaths from the disease in the United States by 2024.

“Prostate cancer that has spread to the lungs, liver, and bones has the greatest impact on survival,” says lead study author Ryan Serio, MD, a postdoctoral assistant professor of medicine at Weill Cornell Medicine. When prostate cancer is confined to the primary tumor, survival is nearly 100%. Once the cancer has spread, or metastasized, a patient’s chance of survival drops to less than 40%.

A better understanding of prostate cancer metastasis provides opportunities for better treatments, says Dr. Nowak, who is also an assistant professor. Tri-Institutional PhD Program in Computational Biology and Medicine and a member Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College.

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 Dr. 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 researchers 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 to insert a “barcode,” or unique genetic marker, that could then be edited with CRISPR technology.

This barcode, combined with tools such as genetic sequencing and bioluminescence imaging, allowed the researchers to track the origins and movements of prostate cancer clones—cells that share the same genetic mutations and originate from the original cancer cell as they grow, proliferate, and spread. They followed the clones until the mice were 60 weeks old.

“With barcoding, we were able to track clonal cells as they spread to different metastatic sites throughout the body,” Dr. Serio said. The researchers were able to identify the clonal cells responsible for cancer spread and the patterns of spread. For example, they observed that although the primary tumor contained many prostate cancer cells, most metastases began with a small number of aggressive clones that migrated from the tumor to the bones, liver, lungs and lymph nodes.

They also observed that once most cancer cells spread to an organ, they tend to stay there rather than spread to another site, with only a few closely related cells promoting additional spread. “These dispersal patterns, or seeding topologies, in mice mirror those observed in humans.“Dr. Serio said:

“We were very excited to find that the metastasis pathways in our models matched so well, to some extent, human cancer seeding,” Dr. Nowak said. “Mapping metastatic cell trajectories using our techniques gives us a great start in getting to the bottom of how this deadly cancer spreads.”

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with outside organizations to promote scientific innovation and provide expert guidance. The institution makes these disclosures publicly available to ensure transparency. See profile for this information Dr. David Nowak.

The research described in this story was supported in part through grants from the National Cancer Institute and the National Institute of General Medical Sciences, both part of the National Institutes of Health. R01CA272466 and R35GM127070.