Dynamic glycoprotein hyposialylation promotes chemotherapy evasion and metastatic seeding of quiescent circulating tumor cell clusters in breast cancer.
Academic Article
Overview
abstract
Most of the circulating tumor cells (CTCs) are detected as single cells, whereas a small proportion of CTCs in multicellular clusters with stemness properties possess 20-100 times higher metastatic propensity than the singles. Here we report that CTC dynamics in both singles and clusters in response to therapies predict overall survival for breast cancer. Chemotherapy-evasive CTC clusters are relatively quiescent with a specific loss of ST6GAL1-catalyzed α2,6-sialylation in glycoproteins. Dynamic hyposialylation in CTCs or deficiency of ST6GAL1 promotes cluster formation for metastatic seeding and enables cellular quiescence to evade paclitaxel treatment in breast cancer. Glycoproteomic analysis reveals newly identified protein substrates of ST6GAL1, such as adhesion or stemness markers PODXL, ICAM1, ECE1, ALCAM1, CD97, and CD44, contributing to CTC clustering (aggregation) and metastatic seeding. As proof-of-concept, neutralizing antibodies against one newly identified contributor, PODXL, inhibit CTC cluster formation and lung metastasis associated with paclitaxel treatment for triple-negative breast cancer.
