Researchers have identified genes that breast cancer cells may use to survive in the bloodstream after escaping the low-oxygen regions of a tumor, according to a novel study published by Godet et al in Nature Communications. Each of the genes may serve as a potential therapeutic target to prevent cancer recurrence.
Deep in a tumor full of rapidly dividing cells, cancer cells are faced with hypoxic conditions. Cancer cells that survive these tough environments end up making their way to the oxygen-rich bloodstream and often metastasizing elsewhere in the body.
Study Methods, Findings, and Implications
In the study, the researchers identified 16 genes responsible for this protection from reactive oxygen species, “which is a stress that occurs when the cells enter the bloodstream. Although the hypoxic cells are localized in what we call the perinecrotic region of a tumor—meaning they’re sitting right next to dead cells—we think that they're able to migrate into higher [oxygen] levels where they can actually find the bloodstream,” explained senior study author Daniele Gilkes, PhD, Assistant Professor of Oncology at Johns Hopkins University, Baltimore.
“Cells able to survive super-low oxygen concentrations do a better job of surviving in the bloodstream. This is how, even after a tumor is removed, we sometimes find that cancer cells have set up elsewhere in the body. Lower levels of oxygen in a tumor correlate with worse prognosis,” she continued.
The researchers sought to better understand the factors that help these posthypoxic cells survive in an environment that would kill other cancer cells as well as which genes were being turned on to facilitate survival. In laboratory studies, they color-coded hypoxic cells green, then applied spatial transcriptomics to identify which genes were turned on in the perinecrotic region and stayed on when the cells migrated to more oxygenated tumor regions. The researchers then compared cells in the primary tumors of mice with those that had entered the bloodstream or the lungs. A subset of hypoxia-induced genes continued to be expressed long after cancer cells escaped the initial tumor.
“The results suggest the potential for a sort of memory of exposure to hypoxic conditions,” said Dr. Gilkes.
The researchers demonstrated a disparity between what occurs in laboratory models and what happens in the human body. When cells in a dish are hypoxic and returned to high levels of oxygen in a short time, they tend to stop expressing the hypoxia-induced genes and return to a normal state. However, in tumors, hypoxia can be more of a chronic condition rather than acute. When the researchers exposed cells to hypoxia for a longer period of about 5 days, they mimicked what was happening in the mouse models.
Focus on MUC1
The results were particularly predictive for triple-negative breast cancer, which has a high rate of recurrence. The researchers discovered that patient biopsies from triple-negative breast cancer that had recurred within 3 years had higher levels of a protein called MUC1.
As part of their research model, the researchers blocked MUC1 using a compound called GO-203 to determine whether it would reduce the spread of breast cancer cells to the lung. Their aim was to specifically eliminate aggressive, posthypoxic metastatic cells.
“If we reduced the level of MUC1 in these hypoxic cells, they were no longer able to survive in the bloodstream or in presence of reactive oxygen species, and they formed fewer metastases in mice,” Dr. Gilkes underscored. However, there may be other factors at play, and additional research will be needed to validate the findings across different cancer types.
A phase I/II clinical trial targeting MUC1 in patients with advanced cancers across a variety of solid tumor types—including those found in breast, ovarian, and colorectal cancers—is currently ongoing.
Disclosure: The research in this study was funded by The Jayne Koskinas Ted Giovanis Foundation for Health and Policy, the National Cancer Institute (NCI)/Sidney Kimmel Comprehensive Cancer Center Core grant, an NCI grant, and the National Cancer Center. For full disclosures of the study authors, visit nature.com.
