Johns Hopkins Kimmel Cancer Center scientists have found that breast cancer cells use 16 genes to survive in the bloodstream after they move out from low-oxygen parts of the tumor. Each gene is a potential target for the therapeutic intervention to prevent cancer recurrence and (MUC1) has already entered clinical trials. This study is published in Nature Communications.
Cancer cells that dwell deep in a tumor, rapidly divide the cancer cells and adapt to a hypoxic (low-oxygen) environment. These tough internal environments, adds lead study author Daniele Gilkes, Ph.D., assistant professor of oncology at Johns Hopkins, ‘end up selecting cancer cells that survived those places, go looking for what they missed, migrate back slowly but surely to the oxygen-rich bloodstream, and then often they seed metastasis in other parts of the body.’ Gilkes said the team found 16 genes that can protect the cells from reacting positively to reactive oxygen species (a stress that occurs when cells enter the bloodstream).
‘Developing organisms cannot tolerate prolonged hypoxia,’ Harrison says. ‘We know that the hypoxic cells are contained in what we say is the perinecrotic region of a tumor, meaning that they’re right next to the necrotic [dead] cells, but we think the hypoxic cells can move out of these perinecrotic cells into areas that have a higher oxygen gradient where they can get to the blood.’
Cells that are better at surviving super-low oxygen concentrations also thrive in the bloodstream. “In a tumor, lower oxygen levels are associated with a worse prognosis.” Keen to understand what keeps these post-hypoxia cells alive in a cell-killing environment and which genes are being turned on to survive, the scientists embarked on the work.
In the lab, Gilkes’ team has color-coded these hypoxic cells green and applied a technique known as spatial transcriptomics to identify the genes that are turned on at the perinecrotic site and the turned-on genes remain on while nearby cells migrate to less stagnant areas of the animal. Cells in the primary tumors of mice were compared to cells that had migrated into the bloodstream or lungs. These cells continue to express a subset of hypoxia-induced genes long after cancer cells have escaped the initial tumor. Gilkes says, “The results imply the possibility of a memory of being exposed to hypoxic conditions.”
Mystery solved; the new research described how the results derived from laboratory models vary from the reality of the human body. For example, if cells in a dish go hypoxic, and then return to high oxygen levels very quickly (say in a picture), they usually stop expressing (hypoxia-induced) genes and go back to normal. But in tumors, hypoxia can be more of a chronic, not acute. “So, when I first took cells and exposed them to hypoxia for a shorter period of three days or so, we were mimicking the mouse models,” Gilkes said.
Results were particularly predictive for triple-negative breast cancer (TNBC), which has a high rate of recurrence. In TNBC recurred within 3 years, patient biopsies had higher levels of a protein, MUC1, the researchers found. In their research model, Gilkes and colleagues make use of a compound called GO-203, which blocks MUC1, and they see if it would prevent breast cancer cell spread to the lung. They were looking to target the very specific, very bad, aggressive, post-hypoxic metastatic cells.
“We were able to reduce the level of MUC1 in these hypoxic cells, and they can’t survive in the bloodstream or in the presence of reactive oxygen species, and they make fewer metastases in mice,” Gilkes says. We’re currently pursuing a phase I/II clinical trial focusing on MUC1 for patients with their advanced cancers in a number of solid tumors, including breast, ovarian, and colorectal cancer, says Gilkes.
Reference: Godet I, Oza HH, Shi Y, et al. Hypoxia induces ROS-resistant memory upon reoxygenation in vivo promoting metastasis in part via MUC1-C. Nat Commun. 2024;15:8416. doi: 10.1038/s41467-024-28416-9
