预计胰腺导管腺癌（PDAC）将很快超过结直肠癌成为美国男性和女性的癌症死亡主要原因，仅次于肺癌。PDAC的致死性由于晚期诊断和低效疗法而产生。PDAC的复杂生物学涉及多种细胞组分，包括携带细胞间分子信息的外泌体。因此，接受者细胞可能会被重新编程，从而影响肿瘤发生。Rab27a是一个负责外泌体生物成熟的GTP酶。因此，剖析调控Rab27a的表达和控制外泌体生成的机制可以提供关于调控PDAC进展的分子基础的基本见解。 为了评估调控PDAC中Rab27a表达的机制，我们使用PDAC细胞系。这些发现在PDAC的基因工程小鼠模型（GEMMs）和人样品中得到了验证，这些验证了这些发现的生物学意义。 在这项研究中，我们在人类PDAC样本和GEMMs中证明了Rab27a的表达随着该疾病的发展而降低，并且Rab27a的缺失促进了疾病的进展。更重要的是，我们证明了Rab27a的表达在PDAC中受到表观遗传调控。使用去甲基化剂处理仅对人类PDAC细胞系特异性地增加了Rab27a的表达。我们发现SMC3，凝聚素复合物的一个组分，调控PDAC中Rab27a的表达。SMC3的甲基化存在于人类PDAC标本中，使用去甲基化剂处理可以增加人类PDAC细胞系中的SMC3表达。最重要的是，高水平的SMC3甲基化与PDAC的糟糕预后相关。从机械上讲，我们在Rab27a基因中识别了一个能够招募SMC3并调控Rab27a表达的增强子区域。 总体而言，我们剖析了在PDAC进展过程中调控Rab27a表达的机制，并对疾病预后产生了影响。 © 2023. BioMed Central Ltd.，Springer Nature一部分。

Pancreatic ductal adenocarcinoma (PDAC) is expected to soon surpass colorectal cancer as a leading cause of cancer mortality in both males and females in the US, only lagging behind lung cancer. The lethality of PDAC is driven by late diagnosis and inefficient therapies. The complex biology of PDAC involves various cellular components, including exosomes that carry molecular information between cells. Thus, recipient cells can be reprogrammed, impacting tumorigenesis. Rab27a is a GTPase responsible for the last step of exosomes biogenesis. Hence, dissecting the mechanisms that regulate the expression of Rab27a and that control exosomes biogenesis can provide fundamental insights into the molecular underpinnings regulating PDAC progression.To assess the mechanism that regulates Rab27a expression in PDAC, we used PDAC cell lines. The biological significance of these findings was validated in PDAC genetically engineered mouse models (GEMMs) and human samples.In this work we demonstrate in human PDAC samples and GEMMs that Rab27a expression decreases throughout the development of the disease, and that Rab27a knockout promotes disease progression. What is more, we demonstrate that Rab27a expression is epigenetically regulated in PDAC. Treatment with demethylating agents increases Rab27a expression specifically in human PDAC cell lines. We found that SMC3, a component of the cohesin complex, regulates Rab27a expression in PDAC. SMC3 methylation is present in human PDAC specimens and treatment with demethylating agents increases SMC3 expression in human PDAC cell lines. Most importantly, high levels of SMC3 methylation are associated with a worse prognosis in PDAC. Mechanistically, we identified an enhancer region within the Rab27a gene that recruits SMC3, and modulates Rab27a expression.Overall, we dissected a mechanism that regulates Rab27a expression during PDAC progression and impacts disease prognosis.© 2023. BioMed Central Ltd., part of Springer Nature.