TY - JOUR
T1 - Clinical importance of high-mannose ,fucosylated, and complex N-glycans in breast cancer metastasis
AU - Scupakova, K.
AU - Adelaja, O.T.
AU - Balluff, B.
AU - Ayyappan, V.
AU - Tressler, C.M.
AU - Jenkinson, N.M.
AU - Claes, B.S.R.
AU - Bowman, A.P.
AU - Cimino-Mathews, A.M.
AU - White, M.J.
AU - Argani, P.
AU - Heeren, R.M.A.
AU - Glunde, K.
N1 - Funding Information:
Special thanks to all the patients and families whose selfless generosity made this research possible. We would also like to thank Helen Fedor in the Johns Hopkins Oncology Tissue Service Core Facility for TMA sectioning and Hang Nguyen for manuscript editing. This work was funded by the NIH of the United States of America — i.e., R01 CA213428, R01 CA213492, and T32 CA193145. This work was also supported by the Dutch province of Limburg as part of the “LINK” program. BB acknowledges financial support of the European Union (ERA-NET TRANSCAN 2; grant no. 643638).
Funding Information:
FUNDING. NIH grants R01CA213428, R01CA213492, R01CA264901, T32CA193145, Dutch Province Limburg “LINK”, European Union ERA-NET TRANSCAN2-643638.
Funding Information:
NIH grants R01CA213428, R01CA213492, R01CA264901, T32CA193145, Dutch Province Limburg ?LINK?, European Union ERA-NET TRANSCAN2-643638. Special thanks to all the patients and families whose selfless generosity made this research possible. We would also like to thank Helen Fedor in the Johns Hopkins Oncology Tissue Service Core Facility for TMA sectioning and Hang Nguyen for manuscript editing. This work was funded by the NIH of the United States of America ? i.e., R01 CA213428, R01 CA213492, and T32 CA193145. This work was also supported by the Dutch province of Limburg as part of the ?LINK? program. BB acknowledges financial support of the European Union (ERA-NET TRANSCAN 2; grant no. 643638).
Publisher Copyright:
© 2021 American Society for Clinical Investigation. All rights reserved.
PY - 2021/12/22
Y1 - 2021/12/22
N2 - BACKGROUND. Although aberrant glycosylation is recognized as a hallmark of cancer, glycosylation in clinical breast cancer (BC) metastasis has not yet been studied. While preclinical studies show that the glycocalyx coating of cancer cells is involved in adhesion, migration, and metastasis, glycosylation changes from primary tumor (PT) to various metastatic sites remain unknown in patients. METHODS. We investigated N-glycosylation profiles in 17 metastatic BC patients from our rapid autopsy program. Primary breast tumor, lymph node metastases, multiple systemic metastases, and various normal tissue cores from each patient were arranged on unique single-patient tissue microarrays (TMAs). We performed mass spectrometry imaging (MSI) combined with extensive pathology annotation of these TMAs, and this process enabled spatially differentiated cell-based analysis of N-glycosylation patterns in metastatic BC. RESULTS. N-glycan abundance increased during metastatic progression independently of BC subtype and treatment regimen, with high-mannose glycans most frequently elevated in BC metastases, followed by fucosylated and complex glycans. Bone metastasis, however, displayed increased core-fucosylation and decreased high-mannose glycans. Consistently, N-glycosylated proteins and N-glycan biosynthesis genes were differentially expressed during metastatic BC progression, with reduced expression of mannose-trimming enzymes and with elevated EpCAM, N-glycan branching, and sialyation enzymes in BC metastases versus PT. CONCLUSION. We show in patients that N-glycosylation of breast cancer cells undergoing metastasis occurs in a metastatic site-specific manner, supporting the clinical importance of highmannose, fucosylated, and complex N-glycans as future diagnostic markers and therapeutic targets in metastatic BC.
AB - BACKGROUND. Although aberrant glycosylation is recognized as a hallmark of cancer, glycosylation in clinical breast cancer (BC) metastasis has not yet been studied. While preclinical studies show that the glycocalyx coating of cancer cells is involved in adhesion, migration, and metastasis, glycosylation changes from primary tumor (PT) to various metastatic sites remain unknown in patients. METHODS. We investigated N-glycosylation profiles in 17 metastatic BC patients from our rapid autopsy program. Primary breast tumor, lymph node metastases, multiple systemic metastases, and various normal tissue cores from each patient were arranged on unique single-patient tissue microarrays (TMAs). We performed mass spectrometry imaging (MSI) combined with extensive pathology annotation of these TMAs, and this process enabled spatially differentiated cell-based analysis of N-glycosylation patterns in metastatic BC. RESULTS. N-glycan abundance increased during metastatic progression independently of BC subtype and treatment regimen, with high-mannose glycans most frequently elevated in BC metastases, followed by fucosylated and complex glycans. Bone metastasis, however, displayed increased core-fucosylation and decreased high-mannose glycans. Consistently, N-glycosylated proteins and N-glycan biosynthesis genes were differentially expressed during metastatic BC progression, with reduced expression of mannose-trimming enzymes and with elevated EpCAM, N-glycan branching, and sialyation enzymes in BC metastases versus PT. CONCLUSION. We show in patients that N-glycosylation of breast cancer cells undergoing metastasis occurs in a metastatic site-specific manner, supporting the clinical importance of highmannose, fucosylated, and complex N-glycans as future diagnostic markers and therapeutic targets in metastatic BC.
KW - GLYCOSYLATION
KW - TUMOR
KW - EPCAM
KW - HETEROGENEITY
KW - EXPRESSION
KW - ADHESION
KW - TARGET
KW - LUNG
KW - MYC
U2 - 10.1172/jci.insight.146945
DO - 10.1172/jci.insight.146945
M3 - Article
C2 - 34752419
SN - 2379-3708
VL - 6
JO - JCI INSIGHT
JF - JCI INSIGHT
IS - 24
M1 - e146945
ER -