胰腺神经内分泌肿瘤（PanNET）代表具有不同临床结果的分化良好的内分泌肿瘤。使用当前的肿瘤分级系统预测患者的结果具有挑战性。此外，针对 PanNET 的传统全身治疗方案（例如生长抑素类似物或细胞毒性化疗）非常有限。为了解决这些问题，我们使用综合蛋白质组学对 PanNET 进行了表征，并确定了四种亚型。两种蛋白质组亚型显示出高复发率，表明当前分类忽略了临床侵袭性。缺氧和炎症途径在临床侵袭性亚型中显着丰富。详细分析揭示了缺氧条件下通过糖酵解上调和氧化磷酸化下调进行的代谢适应。炎症特征分析表明，免疫抑制分子在免疫热肿瘤中富集，可能是免疫治疗的靶点。在这项研究中，我们表征了分化良好的 PanNET 的临床侵袭性蛋白质组亚型，并确定了候选治疗靶点。© 2024 由 Elsevier Inc. 出版。

Pancreatic neuroendocrine tumors (PanNETs) represent well-differentiated endocrine neoplasms with variable clinical outcomes. Predicting patient outcomes using the current tumor grading system is challenging. In addition, traditional systemic treatment options for PanNETs, such as somatostatin analogs or cytotoxic chemotherapies, are very limited. To address these issues, we characterized PanNETs using integrated proteogenomics and identified four subtypes. Two proteomic subtypes showed high recurrence rates, suggesting clinical aggressiveness that was missed by current classification. Hypoxia and inflammatory pathways were significantly enriched in the clinically aggressive subtypes. Detailed analyses revealed metabolic adaptation via glycolysis upregulation and oxidative phosphorylation downregulation under hypoxic conditions. Inflammatory signature analysis revealed that immunosuppressive molecules were enriched in immune hot tumors and might be immunotherapy targets. In this study, we characterized clinically aggressive proteomic subtypes of well-differentiated PanNETs and identified candidate therapeutic targets.© 2024 Published by Elsevier Inc.