Molecular mechanisms underlying circulating tumor cell aggregation

Circulating tumor cells (CTCs) pose continuous and persistent threats to create new metastases albeit at an unknown, extremely low efficiency. Compared to single CTCs, clusters of multicellular CTCs possess 50-100 times higher metastatic capacity, create more polyclonal metastasis, and correlate with worse prognosis. Our previous studies demonstrated that CTC clusters are derived from individual cell aggregation instead of collective migration and cohesive shedding. The objectives of this proposal are to identify new drivers of the tumor cluster formation, and to elucidate the role and mechanisms how they contribute to enhanced stemness, improved survival and reduced anoikis, and effective metastasis of triple negative breast cancer, using multiple human PDXs and CTC lines as well as mouse tumor models. Based on the molecular understanding, we will also determine proof-in-principle targeting strategies to block CTC cluster formation and prevent new metastasis. The collaborative team includes Dr. Huiping Liu (Northwestern University) with expertise in CTC and cancer stemness, breast oncologist Dr. Massimo Cristofanilli (Northwestern University), imaging expert Dr. Constadina Arvanitis (Northwestern University), and bioinformaticist and structural biologist Dr. Yang Shen (Texas A & M).