American Association for Cancer Research
Browse
- No file added yet -

Supplementary Video S18 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer

Download (2.23 MB)
media
posted on 2023-08-09, 13:20 authored by Nurmaa K. Dashzeveg, Yuzhi Jia, Youbin Zhang, Lorenzo Gerratana, Priyam Patel, Asif Shajahan, Tsogbadrakh Dandar, Erika K. Ramos, Hannah F. Almubarak, Valery Adorno-Cruz, Rokana Taftaf, Emma J. Schuster, David Scholten, Michael T. Sokolowski, Carolina Reduzzi, Lamiaa El-Shennawy, Andrew D. Hoffmann, Maroua Manai, Qiang Zhang, Paolo D'Amico, Parastoo Azadi, Karen J. Colley, Leonidas C. Platanias, Ami N. Shah, William J. Gradishar, Massimo Cristofanilli, William A. Muller, Brian A. Cobb, Huiping Liu

Supplementary Video S18 shows the clustering video of siECE1 transfected ST6WT cells presented in Supplementary Fig.S14B.

History

ARTICLE ABSTRACT

Most circulating tumor cells (CTC) are detected as single cells, whereas a small proportion of CTCs in multicellular clusters with stemness properties possess 20- to 100-times higher metastatic propensity than the single cells. 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 a 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. This study discovers that dynamic loss of terminal sialylation in glycoproteins of CTC clusters contributes to the fate of cellular dormancy, advantageous evasion to chemotherapy, and enhanced metastatic seeding. It identifies PODXL as a glycoprotein substrate of ST6GAL1 and a candidate target to counter chemoevasion-associated metastasis of quiescent tumor cells.

Usage metrics

    Cancer Discovery

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC