Compartment resolved proteomics reveals a dynamic matrisome in a biomechanically driven model of pancreatic ductal adenocarcinoma.
Compartment resolved proteomics reveals a dynamic matrisome in a biomechanically driven model of pancreatic ductal adenocarcinoma.
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DOI：
10.1016/j.regen.2018.03.002
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发表时间：
2018-03-01
期刊：
影响因子：
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通讯作者：
Hansen, Kirk C
中科院分区：
文献类型：
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作者：
Barrett, Alexander S;Maller, Ori;Hansen, Kirk C
胰腺导管腺癌 (PDAC) 的特点是存在严重的纤维化成分，会影响治疗、改变免疫细胞特征并导致患者死亡。研究表明，在此过程的早期，组织生物力学的动态变化在支持胰腺癌的发生和进展中发挥着不可或缺的作用。尽管人们承认其重要性，但在 PDAC 进展过程中基质成分如何变化的详细视图仍然很大程度上未知。为了模拟临床上观察到的准间充质表型和显着的促纤维增生反应，我们利用了由 KrasG12D 突变和 Tgfbr2 表达缺失驱动的 PDAC 基因工程小鼠模型。隔室解析蛋白质组学的应用表明，该 KTC 模型中的 PDAC 进展与动态基质改变相关，而动态基质改变表明伤口愈合程序。我们发现了一种早期临时基质细胞纤维化，伴有巨噬细胞活化和浸润的标志物，与伤口愈合的炎症阶段一致。 20 周时，观察到增殖表型，成纤维细胞标记物增加、胶原蛋白进一步沉积以及基底膜和天然细胞标记物的损失。
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a severe fibrotic component that compromises treatment, alters the immune cell profile and contributes to patient mortality. It has been shown that early on in this process, dynamic changes in tissue biomechanics play an integral role in supporting pancreatic cancer development and progression. Despite the acknowledgement of its importance, a granular view of how stromal composition changes during the course of PDAC progression remains largely unknown. To mimic the quasi-mesenchymal phenotype and pronounced desmoplastic response observed clinically, we utilized a genetically engineered mouse model of PDAC that is driven by a KrasG12D mutation and loss of Tgfbr2 expression. Application of compartment resolved proteomics revealed that PDAC progression in this KTC model is associated with dynamic stromal alterations that are indicative of a wound healing program. We identified an early provisional matricellular fibrosis that was accompanied by markers of macrophage activation and infiltration, consistent with the inflammatory phase of wound healing. At 20 weeks a proliferative phenotype was observed with increased fibroblast markers, further collagen deposition and loss of basement membrane and native cell markers.