Soluble E-cadherin drives brain metastasis in aggressive inflammatory breast cancer

Researchers at The University of Texas MD Anderson Cancer Center have identified a targetable driver of brain metastases in patients with aggressive inflammatory breast cancer.

The study uncovers a novel role for soluble E-cadherin (sEcad) in promoting tumor invasion while resisting cancer cell death and triggering brain inflammation via the CXCR2 signaling pathway. The results suggest that targeting sEcad or the CXCR2 pathway could treat or prevent brain metastasis.

The study, published in Neuro-Oncology, was led by Xiaoding Hu, M.D., Ph.D., instructor of Breast Medical Oncology, and Bisrat Debeb, D.V.M., Ph.D., associate professor of Breast Medical Oncology.

This readily measurable blood biomarker plays a key role in driving brain metastasis. Targeting this pathway has tremendous potential to treat and prevent this serious complication and could help guide future therapies."

Bisrat Debeb, D.V.M., Ph.D., Associate Professor of Breast Medical Oncology

What prompted the researchers' interest in E-cadherin in brain metastasis?

Brain metastasis is a common complication of advanced breast cancer, with a particularly high risk in inflammatory breast cancer. However, there are no effective therapies because the underlying mechanisms remain poorly understood.

Previous work by the Debeb lab showed that patients with elevated levels of sEcad in their blood tend to have an increased risk of brain metastasis, earlier metastasis and poorer overall survival. Therefore, the researchers wanted to further understand the role of sEcad.

What did the researchers learn in this study?

In this study, preclinical models of inflammatory breast cancer overexpressing sEcad showed higher metastatic burden, reduced survival and increased metastasis to the brain. The researchers found that sEcad activates the CXCR2 pathway, which creates a feedback loop that helps cancer cells evade cell death and fosters an inflammatory, pro-metastatic environment.

Using a CRCX2 inhibitor significantly reduced metastasis and extended survival in these models, suggesting its potential as a therapeutic target.

What does this mean for patients with inflammatory breast cancer?

This study identifies sEcad and the CRCX2 pathway as essential for brain metastasis, suggesting that blocking any part of that pathway could slow or prevent cancer spread.

Further, monitoring levels of sEcad in the blood could be a way to identify patients most at risk of brain metastasis, and treatment with a CRCX2 inhibitor seems to be a potential therapeutic strategy for these patients. Further studies are needed to confirm these findings and determine appropriate treatment approaches.