Cancer cells that survive in low-oxygen (hypoxic) regions of tumors utilize specific genes to facilitate metastasis, according to researchers at the Johns Hopkins Kimmel Cancer Center. The team identified 16 genes that breast cancer cells use to survive in the bloodstream after escaping hypoxic tumor regions. These genes represent potential therapeutic targets to prevent cancer recurrence, with one, MUC1, already under evaluation in clinical trials.
Hypoxia and Metastasis
Hypoxia, a condition of low oxygen, occurs deep within tumors due to rapid cell division. Cancer cells that endure these harsh conditions can migrate to oxygen-rich areas, such as the bloodstream, and initiate metastasis. According to Daniele Gilkes, Ph.D., assistant professor of oncology at Johns Hopkins, cells able to survive super-low oxygen concentrations do a better job of surviving in the bloodstream, which correlates with worse prognosis.
The team sought to identify the mechanisms that allow post-hypoxic cells to thrive in environments that would kill other cancer cells, focusing on genes activated to facilitate survival.
Gene Identification and Spatial Transcriptomics
Using spatial transcriptomics, the researchers identified genes activated in the perinecrotic region (adjacent to dead cells) of tumors that remained active even after cells migrated to more oxygenated areas. They compared cells from primary tumors in mice with those found in the bloodstream or lungs, revealing a subset of hypoxia-induced genes that persisted long after the cells left the initial tumor.
"The results suggest the potential for a sort of memory of exposure to hypoxic conditions," says Gilkes.
Disparity Between In Vitro and In Vivo Models
The study addressed discrepancies between laboratory models and the human body. While cells in a dish exposed to short-term hypoxia tend to revert to normal gene expression upon reoxygenation, tumors experience chronic hypoxia. The team found that prolonged hypoxia exposure (five days) mimicked the conditions in mouse models, leading to sustained expression of metastasis-promoting genes.
MUC1 and Triple-Negative Breast Cancer
The research showed that patient biopsies from triple-negative breast cancer (TNBC) that recurred within three years had higher levels of the protein MUC1. TNBC is known for its high recurrence rate, making this finding particularly significant.
Therapeutic Intervention
To assess the role of MUC1 in metastasis, the researchers blocked MUC1 using a compound called GO-203. "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," Gilkes says. This suggests that targeting MUC1 could reduce the spread of aggressive, post-hypoxic metastatic cells.
Clinical Trial
A Phase I/II clinical trial is currently underway, targeting MUC1 in patients with advanced cancers across various solid tumor types, including breast, ovarian, and colorectal cancer. This trial aims to evaluate the safety and efficacy of MUC1 inhibition as a cancer therapy.
