Maastricht MultiModal Molecular Imaging Institute (M4I), Maastricht University, Maastricht, The Netherlands.
The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research.
JCI Insight. 2021 Dec 22;6(24):e146945. doi: 10.1172/jci.insight.146945.
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.
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.
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.
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 high-mannose, fucosylated, and complex N-glycans as future diagnostic markers and therapeutic targets in metastatic BC.
NIH grants R01CA213428, R01CA213492, R01CA264901, T32CA193145, Dutch Province Limburg "LINK", European Union ERA-NET TRANSCAN2-643638.
尽管异常糖基化已被认为是癌症的一个标志，但临床乳腺癌（BC）转移中的糖基化尚未得到研究。虽然临床前研究表明，癌细胞的糖萼涂层参与了黏附、迁移和转移，但患者原发肿瘤（PT）到各种转移部位的糖基化变化仍不清楚。
我们从我们的快速尸检计划中调查了 17 名转移性 BC 患者的 N-糖基化谱。每位患者的原发性乳腺肿瘤、淋巴结转移、多个全身转移和来自每个患者的各种正常组织核心都排列在独特的单个患者组织微阵列（TMA）上。我们进行了质谱成像（MSI），并对这些 TMA 进行了广泛的病理学注释，这一过程使我们能够对转移性 BC 中的 N-糖基化模式进行基于细胞的空间差异分析。
N-聚糖丰度在转移性进展过程中增加，与 BC 亚型和治疗方案无关，高甘露糖糖基化在 BC 转移中最常升高，其次是岩藻糖基化和复杂糖基化。然而，骨转移显示核心岩藻糖基化增加，高甘露糖糖基化减少。一致地，在转移性 BC 进展过程中，N-糖基化蛋白和 N-糖基化生物合成基因表达不同，与 PT 相比，甘露糖修剪酶表达降低，EpCAM、N-糖基化分支和唾液酸化酶表达升高。
我们在患者中表明，转移性乳腺癌细胞的 N-糖基化以转移性部位特异性的方式发生，支持高甘露糖、岩藻糖基化和复杂 N-聚糖作为转移性 BC 未来诊断标志物和治疗靶点的临床重要性。
美国国立卫生研究院授予 R01CA213428、R01CA213492、R01CA264901、T32CA193145、荷兰林堡省“LINK”、欧盟 ERA-NET TRANSCAN2-643638 资助。
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