Shown are metastatic tumor cells (blue) with neuroinflammatory cells (green and red) in the brain. [Image from Yale University]
“Once tumors metastasize in the brain, most drug therapies are no longer effective,” senior author on the study Don Nguyen said. “There’s a big question whether that’s because those drugs are not getting into the brain, which is a difficult place for drugs to penetrate, or because additional mechanisms are at work.”
The method involved transferring human tumor cells into mice that didn’t have an immune system. Emily Wingrove and Zongzhi Liu, co-authors on the study, developed a system for precise RNA sequencing of xenograft tissue samples to see gene expressions in the human tumor cells and mouse cells. The researchers say that the gene expression is responsible for producing proteins that can shape a cell for its roles within the body.
They experimented in mice using human lung cancer cell lines that could quickly metastasize to the brain. Then the researchers could analyze the changes in gene expression as the tumors started to grow and compare the expression to healthy brain tissues.
The scientists discovered a set of changes in the gene expression.
“We’re seeing changes in thousands of genes induced by the tumor microenvironment,” Wingrove said in a press release. “I would never have imagined that so many genes change just when you grow cells in a different context.”
Once the researchers were able to validate the findings, they expanded by analyzing other xenograft models of brain metastatic melanoma and breast cancer. The study was also able to reveal new methods for identifying new biomarkers that could help with early detection of brain metastasis.
The research was published in the journal Cell Reports and was funded by Yale Lung and Skin Cancer SPORE grants and a grant from the Beatrice Kleinberg Neuwirth Fund.
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