Project Summary Great progress has been made in treating cancer, however metastasis for most patients remains incurable, causing up to 90% of cancer deaths. Metastasis accounts for 8 million deaths per year worldwide and very few therapeutic options are available that prevent the spread of cancer. The metastatic process often begins with clusters of cancer cells that leave the primary tumor and enter circulation in the blood stream. Upon dissemination into distant organs, these clusters survive and give rise to proliferating metastatic tumors, which in turn can lead to additional metastases. While virtually all oncology-related drugs aim to kill cancer cells within a primary tumor, no drugs are available to target metastatic cell clusters in transit. As a consequence, it is nearly impossible to block or prevent the metastatic cascade. However, it has been recently shown that targeting these circulating highly metastatic cancer cell clusters can significantly reduce the spread of cancer. This discovery strengthens the urgent need to identify unique drug targets specific to these clusters. We recently developed and produced a microfluidic device that allows the specific capture and characterization of these cancer cell clusters from a patient’s blood sample. Integrated into our technology, we utilize a completely novel dual-capture approach based on a combination of biomimicry and immuno-capture. This dual-capture approach provides a substantial advantage since it biases capturing the most malignant cancer cell clusters. This exciting new technology will enable the focused characterization of these clusters and allow the development of a new class of anti-metastatic therapies, the ‘Cluster-Busters’, that will delay or prevent metastasis in cancer patients. Thus, within this technology validation application, we aim to screen lung cancer patients’ blood samples for circulating cancer cell clusters using our novel capture approach. A substantial advantage imparted by our approach is the collection of viable and naïve clusters allowing phenotypic, genomic, and functional assays. We will characterize these clusters using established tools, such as immunohistochemistry and RNA-sequencing. The conclusion of our study will confirm our technology’s ability to expedite the discovery of novel drug targets.