异常糖基化在胰腺导管腺癌（PDAC）中的作用仍然是一个未充分研究的领域。在本研究中，我们发现ST6GAL1唾液酸转移酶在早期PDAC患者中上调，并在晚期疾病中进一步增加，该酶将α2,6连接的唾液酸添加到N-糖基化蛋白质中。通过使用人类PDAC细胞进行肿瘤异种移植实验，我们阐明了ST6GAL1的肿瘤促进功能。此外，我们开发了具有转基因ST6GAL1在胰腺表达的遗传工程小鼠模型，并发现与仅表达KRASG12D的小鼠相比，具有ST6GAL1和KRASG12D双重表达的小鼠的PDAC进展明显加速。由于ST6GAL1赋予了祖细胞样特性，我们研究了ST6GAL1在腺泡向导管样肉芽肿（ADM）中的作用，这个过程通过重编程腺泡细胞为导管样祖细胞而促进新生物。我们使用多种模型验证了ST6GAL1促进ADM的作用，包括266-6细胞系、GEM衍生的器官样体和组织以及炎症诱导ADM的体内模型。EGFR是ADM的一个关键驱动因子，而ST6GAL1介导的唾液酸化被认为可以激活EGFR。重要的是，具有转基因ST6GAL1表达的小鼠的腺泡细胞和器官样体中EGFR的激活明显增加。这些综合结果突出了涉及胰腺新生物早期阶段的依赖于糖基化的机制。

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that the ST6GAL1 sialyltransferase, which adds α2,6-linked sialic acids to N-glycosylated proteins, is upregulated in patients with early-stage PDAC, and further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft experiments with human PDAC cells. Additionally, we developed a genetically-engineered mouse (GEM) with transgenic expression of ST6GAL1 in the pancreas, and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D have greatly accelerated PDAC progression compared with mice expressing KRASG12D alone. As ST6GAL1 imparts progenitor-like characteristics, we interrogated ST6GAL1's role in acinar to ductal metaplasia (ADM), a process that fosters neoplasia by reprogramming acinar cells into ductal, progenitor-like cells. We confirmed ST6GAL1 promotes ADM using multiple models including the 266-6 cell line, GEM-derived organoids and tissues, and an in vivo model of inflammation-induced ADM. EGFR is a key driver of ADM and is known to be activated by ST6GAL1-mediated sialylation. Importantly, EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression. These collective results highlight a glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.