Paoli Carlotta, Carrer Alessandro
Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy.
Department of Biology, University of Padova, 35129 Padova, Italy.
Cancers (Basel). 2020 Sep 12;12(9):2606. doi: 10.3390/cancers12092606.
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.
胰腺导管腺癌（PDA）的致癌过程按照多步骤演变进行，在此过程中，该疾病会获得越来越具侵袭性的病理特征。另一方面，对疾病起源的研究较少。解读导致致癌转化的一系列事件对于设计早期诊断策略以及应对肿瘤发生至关重要。谱系追踪实验表明，胰腺癌细胞病变起源于腺泡细胞，这是胰腺上皮中一种高度特化的细胞类型。原代腺泡细胞可以在体外作为类器官样三维球体存活，在不同的细胞自主性和非细胞自主性刺激下，这些球体可以转分化为具有明确导管形态的细胞。这一事件被称为腺泡-导管化生，概括了疾病起始的组织学和分子特征。在这里，我们将从历史和技术角度讨论原代胰腺腺泡细胞的分离和培养。胰腺癌研究的影响也将进行讨论。特别是，我们将剖析转录、表观遗传和代谢重编程在肿瘤起始中的作用，并展示如何使用体外腺泡细胞培养对其进行建模。最后，将对使用器官型培养描述的PDA起始机制进行综述。
