了解与前列腺癌（PCa）进展和对激素治疗的耐受性相关的分子特征对于确定可用于治疗晚期疾病并延长患者生存的新靶点至关重要。尽管糖链在细胞表面具有高密度，因此具有极大的生物标志物和治疗靶点潜力，但在晚期PCa的背景下，糖基组仍相对未被开发。我们使用成像质谱技术（IMS）在131名代表PCa主要疾病状态的患者的肿瘤组织中进行N-连接糖基的省略，以确定与肿瘤细胞分化丧失、疾病缓解、治疗耐受性和疾病复发以及NE分化（这是治疗失败的主要机制）相关的糖基化变化。我们的结果表明，在PCa的不同阶段中，糖基化模式发生了显着变化，尤其是与疾病缓解相对应的三角和四角糖基的减少，随后是这些结构从耐药性PCa的转变的增加，以及与NE分化相关的复杂的N-糖基的下调。此外，非葡萄糖化和单葡萄糖化的甘露糖9在耐药性PCa中均表现出异常的上调，这可能是有用的治疗靶点，因为这些结构通常不在健康组织中出现。我们的研究结果描述了激素治疗和去势耐受性PCa（CRPC）发展中发生的肿瘤糖基组变化，识别出几种可能用于诊断或治疗目的的糖基标记和特征。© 2023年作者。

An understanding of the molecular features associated with prostate cancer progression (PCa) and resistance to hormonal therapy is crucial for the identification of new targets that can be utilized to treat advanced disease and prolong patient survival. The glycome, which encompasses all sugar polymers (glycans) synthesized by cells, has remained relatively unexplored in the context of advanced PCa despite the fact that glycans have great potential value as biomarkers and therapeutic targets due to their high density on the cell surface. Using imaging mass spectrometry (IMS), we profiled the N-linked glycans in tumor tissue derived from 131 patients representing the major disease states of PCa to identify glycosylation changes associated with loss of tumor cell differentiation, disease remission, therapy resistance and disease recurrence, as well as neuroendocrine (NE) differentiation which is a major mechanism for therapy failure. Our results indicate significant changes to the glycosylation patterns in various stages of PCa, notably a decrease in tri- and tetraantennary glycans correlating with disease remission, a subsequent increase in these structures with the transition to therapy-resistant PCa, and downregulation of complex N-glycans correlating with NE differentiation. Furthermore, both nonglucosylated and monoglucosylated mannose 9 demonstrate aberrant upregulation in therapy-resistant PCa which may be useful therapeutic targets as these structures are not normally presented in healthy tissue. Our findings characterize changes to the tumor glycome that occur with hormonal therapy and the development of castration-resistant PCa (CRPC), identifying several glycan markers and signatures which may be useful for diagnostic or therapeutic purposes.© 2023. The Author(s).