Working to Stop Breast Cancer Turning into Brain Cancer

A new study has taken a significant step forward towards early detection and treatment of breast cancer-associated brain metastasis.

Silicon Biosystems, based in California, reported its DEPArray™ technology platform was instrumental in a key study by researchers at the Houston Methodist Research Institute to better understand how dormant circulating tumor cells (CTCs) in breast cancer become metastatic in the brain.

“Accruing pure, individual cells is a key step in the isolation and genetic profiling of circulating tumor cells and their subtypes,” said Dario Marchetti, Ph.D., Director of the Biomarker Research Program at the Houston Methodist Research Institute. Dr. Marchetti and his research team at Houston Methodist Research Institute, The University of Texas MD Anderson Cancer Center and Baylor College of Medicine reported their findings in the December 3rd issue of the journal Scientific Reports.

Uncovering the Mystery of Tumor-cell Dormancy
Breast cancer patients are often asymptomatic, because CTCs in blood appear to become dormant and clinically undetectable for up to 20 years or more after a primary tumor is surgically removed. The molecular switch from dormancy to a metastatic state depends on the biochem­ical cross-talk between CTCs and the surrounding tumor microenvironment.

Previous studies have uncovered the presence of two tumor markers — urokinase plasminogen activator receptor (uPAR) and integrin B1 (intB1) — that promote tumor cell growth and proliferation when they interact with the extracellular microenvironment of the brain. However, loss of uPAR and intB1 gene expression of these receptor proteins strikingly reduces proliferative signals, causing a shift from an invasive, metastatic state to a dormant state, thus directly implicating these two biomarkers in mechanisms of tumor cell dormancy.

In this study, Dr. Marchetti and his colleagues sorted the uPAR and int B1 CTCs at single-cell level by employing the DEPArray platform and performed mutation analyses to reveal unique genomic signatures of uPAR/int B1 CTC subsets. Using the DEPArray system for cell isolation and subsequent genetic analysis with the Ampli1™ WGA Kit and Ampli1™ QC Kit (Silicon Biosystems), the researchers were able to isolate CTC subsets that (1) did not express a protein known as epithelial cell adhesion molecule (EpCAM), and (2) either did or did not express a combination of the uPAR and int B1 proteins.

We found the EpCAM negative and CTCs expressing uPAR/intB1 were detected in the blood of patients whose breast cancer had metastasized to the brain, while the EpCAM-positive and uPAR/int B1-negative cells did not,” Dr. Marchetti said. “Moreover, we didn’t see any CTCs that were EpCAM-positive in these patients. Thus, we concluded that uPAR/int B1 expression along with EpCAM negativity may be key for allowing or controlling breast cancer recurrence to the brain.  Furthermore, our extensive in vitro/in vivo work studying Heparanase as a molecular determinant of brain metastasis and confirmation of Heparanase expression in single CTCs by the DEPArray, has positioned this platform in a unique position not only to elucidate underpinnings of the brain metastasis but also to foster the clinical utility of Heparanase inhibitors in novel trials as text-book example of precision medicine.”

Dr. Marchetti said upcoming studies would be aimed at better understanding the mechanism responsible for both breast-cancer brain metastasis and dormancy. “We have gained a tremendous amount of information about CTCs grown in our lab, and we can use this knowledge to develop tests for early detecting of these cells and to customize treatments against them.”

Silicon Biosystems is a wholly-owned subsidiary of The Menarini Group, a multinational pharmaceutical, biotechnology and diagnostics company headquartered in Firenze, Italy. The company manufactures and sells the DEPArray system, which enables researchers to automatically identify, quantify, and recover individual rare cells with single-cell precision.

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