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Abstract：
The carcinogenesis of pancreatic ductal adenocarcinoma (PDA) progresses according to multi-step evolution, whereby the disease acquires increasingly aggressive pathological features. On the other hand, disease inception is poorly investigated. Decoding the cascade of events that leads to oncogenic transformation is crucial to design strategies for early diagnosis as well as to tackle tumor onset. Lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a highly specialized cell type in the pancreatic epithelium. Primary acinar cells can survive in vitro as organoid-like 3D spheroids, which can transdifferentiate into cells with a clear ductal morphology in response to different cell- and non-cell-autonomous stimuli. This event, termed acinar-to-ductal metaplasia, recapitulates the histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary pancreatic acinar cells, providing a historical and technical perspective. The impact of pancreatic cancer research will also be debated. In particular, we will dissect the roles of transcriptional, epigenetic, and metabolic reprogramming for tumor initiation and we will show how that can be modeled using ex vivo acinar cell cultures. Finally, mechanisms of PDA initiation described using organotypical cultures will be reviewed.
摘要：
胰腺导管腺癌(PDA)的癌变是按照多步演化的,从而该疾病获得越来越积极的病理特征。另一方面,疾病开始的调查不多。解码导致致癌转化的事件级联对于设计早期诊断策略以及解决肿瘤发作至关重要。谱系追踪实验表明，胰腺癌病变起源于腺泡细胞，胰腺上皮中一种高度特化的细胞类型。原代腺泡细胞可以作为类器官样3D球体在体外存活，它可以转分化为具有清晰导管形态的细胞，以响应不同的细胞和非细胞自主刺激。这个事件,称为腺泡到导管上皮化生，概括了疾病发生的组织学和分子特征。这里,我们将讨论原代胰腺腺泡细胞的分离和培养，提供历史和技术视角。胰腺癌研究的影响也将引起争议。特别是,我们将剖析转录的作用，表观遗传,和代谢重编程为肿瘤启动，我们将展示如何使用离体腺泡细胞培养物进行建模。最后,使用器官型培养描述的PDA启动机制将被审查。
