Abstract 1321: Glycosylation dependent metastatic seeding of circulating tumor cells in breast cancer

Abstract Chemotherapy has been standard of care for triple negative breast cancer for decades; however, how chemotherapy evasion enables metastasis remains elusive and is one of the biggest challenges impacting patient survival in cancer clinics. Circulating tumor cells (CTC) are pivotal component of longitudinal liquid biopsies. Most of the CTCs are detected as a single cell, whereas small proportion of CTCs are found in multicellular clusters which possess 20-100 times higher metastatic potential than single CTCs and corelates with unfavorable survival in breast cancer patients. Here we observed that chemotherapy evasion is linked to the aggregation of CTCs in breast cancer. Chemo-evasive linked aggregated CTCs show specific loss of ST6GAL1-catalyzed alpha2,6-sialylation. Deficiency of ST6GAL1 promotes CTC cluster formation for metastatic seeding and enables cellular quiescence to evade paclitaxel treatment in metastatic breast cancer. Glycoproteomic analysis identified protein substrates of ST6GAL1, such as adhesion and stemness markers PODXL, ICAM1, ECE1, ALCAM1, CD97, and CD44, contributing to CTC clustering (aggregation) and metastatic seeding. As proof-of-concept, neutralizing antibody against one of the most significant contributors, PODXL, inhibits CTC cluster formation and lung metastasis exacerbated by paclitaxel treatment for breast cancer. This study sheds light in the evaluation of chemotherapy response and developed potential therapy approach against chemotherapy resistance. Citation Format: Nurmaa Khund Dashzeveg. Glycosylation dependent metastatic seeding of circulating tumor cells in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1321.