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

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’amicoParastoo Azadi, Karen J. Colley, Leonidas C. Platanias, Ami N. Shah, William J. Gradishar, Massimo Cristofanilli, William A. Muller, Brian A. Cobb, Huiping Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Most circulating tumor cells (CTC) are detected as single cells, whereas a small proportion of CTCs in multicellular clusters with stemness properties possess20-to 100-times higher metastatic propensity than the single cells. Here we report that CTC dynam-ics 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. SIGNIFICANCE: 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 candi-date target to counter chemoevasion-associated metastasis of quiescent tumor cells.

Original languageEnglish (US)
Pages (from-to)2050-2071
Number of pages22
JournalCancer discovery
Volume13
Issue number9
DOIs
StatePublished - Sep 1 2023

Funding

We are grateful to Dr. Susan L. Bellis at the University of Alabama at Birmingham for her insightful feedback and suggestions for this project. We thank Dr. Derek W. Abbott at Case Western Reserve University for generating and providing gRNAs for CRISPR–Cas9-mediated KO of ST6GAL1 (R21 DE025825 to D.W. Abbott and B.A. Cobb). We acknowledge the tremendous support from the North-western Core facilities of CTC Core, the Center for Comparative Medicine, Small Animal Imaging, Microscopy Imaging, Lurie Cancer Center Flow Core, NUSeq Core and Bioinformatics Center, Mouse Histology and Phenotyping Laboratory, and the Pathology Core, as well as the Glycomic Mass Spectrometry Facilities at the Complex Carbohydrate Research Center, the University of Georgia. This work was partially funded by the Department of Defense (BC150596 and BC190982; H. Liu), the NIH (R01CA245699 to H. Liu; R01 GM115234 to B.A. Cobb; and S10OD018530 and R24GM137782 to P. Azadi), the American Cancer Society (ACS127951-RSG-15-025-01-CSM), the Komen Foundation (CCR15332826), the H Foundation, the Lynn Sage Breast Cancer Foundation (H. Liu and N. Dashzeveg), and a Northwestern University start-up grant (H. Liu). L. Gerratana reports personal fees from Eli Lilly, Novartis, Pfizer, GSK, Daiichi Sankyo, AstraZeneca, and Incyte outside the submitted work. V. Adorno-Cruz reports personal fees from Biotheranos-tics, a Hologic company, outside the submitted work. C. Reduzzi reports grants from Menarini Silicon Biosystems outside the submitted work. L. El-Shennaway reports grants from the NIH during the conduct of the study, as well as a patent for the area of exosome therapeutics pending. P. D’Amico reports grants from Roche and other support from Merck & Co. outside the submitted work. A.N. Shah reports personal fees from Gilead and AstraZeneca outside the submitted work. M. Cristofanilli reports personal fees from Menarini and grants from Predicine during the conduct of the study, as well as personal fees from Pfizer, AstraZeneca, and Datar Genetics outside the submitted work. W.A. Muller reports grants from the NIH during the conduct of the study. B.A. Cobb reports grants from the NIH during the conduct of the study, as well as grants from the NIH outside the submitted work. H. Liu reports nonfinancial support and other support from ExoMira Medicine outside the submitted work, as well as a patent for anti-PODXL to block CTC cluster formation and metastatic seeding pending. No disclosures were reported by the other authors.

ASJC Scopus subject areas

  • Oncology

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