Scientists have discovered 16 genes that help breast cancer cells survive in the bloodstream after they escape low-oxygen areas within tumors. These genes could serve as targets for therapy to prevent cancer from returning, with one gene, MUC1, already undergoing clinical trials.
Researchers at the Johns Hopkins Kimmel Cancer Center have found 16 genes that breast cancer cells utilize to thrive in the bloodstream after leaving the low-oxygen zones of a tumor. Each gene presents a possible target for therapy to prevent cancer recurrence, with MUC1 already in clinical trials.
This research was published online on September 28 in the journal Nature Communications.
Within a tumor, where cells divide rapidly, cancer cells encounter a shortage of oxygen, a situation known as hypoxia. Lead author Daniele Gilkes, Ph.D., an assistant professor of oncology at Johns Hopkins, explains that those cancer cells that endure these harsh conditions eventually seek to escape, finding their way into the oxygen-rich bloodstream, where they can spread to other parts of the body.
The team discovered 16 genes that offer protection against reactive oxygen species, a form of stress that arises when cancer cells enter the bloodstream. “While the hypoxic cells are found in what we term the perinecrotic area of a tumor—right next to dead cells—we believe they can migrate towards higher oxygen levels and into the bloodstream,” Gilkes states. She adds, “Cancer cells that can survive extremely low oxygen levels also seem to do better in the bloodstream. This phenomenon explains why we sometimes detect cancer cells elsewhere in the body even after a tumor is surgically removed. Generally, tumors with lower oxygen levels lead to poorer outcomes.”
The scientists aimed to understand what factors contribute to the survival of these post-hypoxic cells in conditions that would typically be lethal for other cancer cells, as well as which genes were activated to support their survival.
In laboratory experiments, Gilkes and her team marked hypoxic cells with a green color and used a technique called spatial transcriptomics to determine which genes were activated in the perinecrotic area and remained active as the cells moved to areas with more oxygen. They compared cells from the primary tumors of mice to those that had entered the bloodstream or the lungs. A subset of genes activated by hypoxia continued to be expressed well after the cancer cells had left the initial tumor.
“These findings indicate there may be a type of memory associated with exposure to hypoxic conditions,” Gilkes remarks.
The new findings highlighted a discrepancy between laboratory conditions and what occurs in human patients, solving a previously perplexing issue for scientists. In experiments, when cells were subjected to hypoxia and then returned to high oxygen levels for a short time, they typically stopped expressing the hypoxia-related genes and reverted to normal behavior. However, in tumors, hypoxia can be a chronic condition rather than a temporary one. When Gilkes’ team exposed cells to hypoxia for extended periods—about five days, in most cases—they were able to replicate the scenarios observed in mouse models.
The results were particularly relevant for triple-negative breast cancer (TNBC), known for its high recurrence rates. The researchers found that biopsies from patients with TNBC who experienced a recurrence within three years exhibited higher levels of a protein named MUC1.
In their study, Gilkes and her team inhibited MUC1 using a compound called GO-203 to assess whether it could limit the migration of breast cancer cells to the lungs, with a focus on eliminating aggressive, post-hypoxic metastatic cells.
“By reducing the level of MUC1 in these hypoxic cells, they could no longer endure in the bloodstream or survive the presence of reactive oxygen species, resulting in fewer metastases in mice,” Gilkes explains. However, she acknowledges that other factors are involved, and further investigation will be required to see if these results hold true across different cancer types.
A phase I/II clinical trial focusing on MUC1 for patients with advanced cancers in various solid tumor types, including breast, ovarian, and colorectal cancers, is currently underway, according to Gilkes.
The study’s co-authors include Inês Godet, Harsh Oza, Yi Shi, Natalie Joe, Alyssa Weinstein, Jeanette Johnson, Michael Considine, Swathi Talluri, Jingyuan Zhang, Reid Xu, Steven Doctorman, Genevieve Stein-O’Brien, Luciane Kagohara, Cesar Santa-Maria, and Elana Fertig from Johns Hopkins, along with Delma Mbulaiteye from the NIDDK STEP-UP Program at the National Institutes of Health.
The research received funding from The Jayne Koskinas Ted Giovanis Foundation for Health and Policy, the NCI/SKCCC Core grant number P50CA006973, NCI grant number 5U01CA253403-03, and the National Cancer Center.
Santa-Maria has received research funding from AstraZeneca, GSK/Tesaro, Merck, Gilead, Celldex, BMS, and Pfizer, and consulting fees from Seattle Genetics. Fertig is a member of the scientific advisory board of Resistance Bio, consults for Merck and Mestag Therapeutics, and has obtained research funding from Abbvie, Inc. and Roche/Genentech. These affiliations are managed by The Johns Hopkins University in accordance with its conflict-of-interest regulations.
