Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
06 09 2023
06 09 2023
Historique:
received:
03
06
2022
revised:
14
04
2023
accepted:
30
05
2023
medline:
7
9
2023
pubmed:
5
6
2023
entrez:
5
6
2023
Statut:
ppublish
Résumé
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. This article is featured in Selected Articles from This Issue, p. 1949.
Identifiants
pubmed: 37272843
pii: 727129
doi: 10.1158/2159-8290.CD-22-0644
pmc: PMC10481132
mid: NIHMS1907326
doi:
Substances chimiques
Paclitaxel
P88XT4IS4D
Glycoproteins
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2050-2071Subventions
Organisme : NCI NIH HHS
ID : R01 CA236904
Pays : United States
Organisme : NCI NIH HHS
ID : UG3 CA256967
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA245699
Pays : United States
Organisme : NIH HHS
ID : S10 OD018530
Pays : United States
Organisme : NIDCR NIH HHS
ID : R21 DE025825
Pays : United States
Organisme : NCI NIH HHS
ID : UH3 CA256967
Pays : United States
Organisme : NIGMS NIH HHS
ID : R24 GM137782
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM115234
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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