Glycoprotein sialylation of CTC clusters in breast cancer metastasis

Metastasis is an aggressive form of cancer cells spreading from its original tissue to distant organs, often incurable and causing 90% of breast cancer deaths. Better understandings of these processes are needed to develop sensitive monitoring and tumor-specific innovative treatment approaches. The traditional dogma visualizes cancer metastasis as a solo dissemination trip of individual tumor cells from primary tumor sites to distant organs, through blood or lymphatics. Our recent research has revealed that circulating tumor cells interact with each other and form a traveling group of orchestrated clusters during their spreading. When more than two tumor cells migrate and circulate together as a clustered band, they have 25-50 times higher likelihood of regenerating tumors in distant organs than solo tumor cells. This proposal is expected to address three overarching challenges of breast cancer: (1) improve our understanding of breast tumors and how they spread, cluster, and metastasize to distant organs, (2) accelerate the development of new diagnostic and prognostic biomarkers using circulating tumor cells in liquid biopsy, and (3) broaden the potential of innovative therapeutic approaches to target tumor cell clusters and eliminate aggressive metastasis of breast cancer. Our project will seek to better understand this development of tumor cell clusters in order to block devastating metastasis. We have discovered that a surface protein CD44 is not only a marker of tumor cells with stem cell properties, but also the driver or director of cellular cluster formation. Two CD44 molecules can extend from two neighboring cells, form a dynamic CD44-CD44 connection bridge between these two cells, and therefore gain advantages for orchestrated cancer metastasis. A sugar modification of CD44 by sialic acids interferes with this CD44 bridge-mediated cluster formation. Our project will also address two additional questions: (1) what is the molecular basis of CD44-directed cellular bridge and cluster formation that influences a successful spreading? Can we target CD44 to block the cluster orchestration of tumor cells and prevent their aggressive progression? (2) Can we distinguish deadly from non-deadly breast cancers by monitoring the cluster band and solo tumor cells in the blood? Ultimately, our work to unveil the biochemistry of the protein CD44 and its sugar modification patterns may lead to new therapeutic interventions and more effective ways to monitor and prevent breast cancer metastasis.