Systematic Comparison of Pancreatic Ductal Adenocarcinoma Models Identifies a Conserved Highly Plastic Basal Cell State.
Systematic Comparison of Pancreatic Ductal Adenocarcinoma Models Identifies a Conserved Highly Plastic Basal Cell State.
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DOI：
10.1158/0008-5472.can-22-1742
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发表时间：
2022-10-04
期刊：
影响因子：
11.2
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中科院分区：
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肿瘤内异质性和细胞可塑性已成为癌症的标志，包括胰腺导管腺癌（PDAC）。由于PDAC预示着可怕的预后，因此更好地理解PDAC中细胞多样性的基础机制至关重要。在这里，我们使用单细胞基因组学研究了PDAC癌细胞在一系列体外和体内生长条件下的细胞异质性。在2D和3D细胞培养模型中异源性细胞显著收缩，但在原位移植后恢复。原位移植可再现地获得在自体PDAC肿瘤中鉴定的细胞状态，包括表现出上皮和间充质基因的共表达和共可及性的基础状态。谱系追踪结合单细胞转录组学显示，基底细胞显示高可塑性原位。这项工作定义了细胞生长条件对表型多样性的影响，并揭示了一种高度可塑性的细胞状态，具有促进PDAC状态转换和促进肿瘤内异质性的能力。这项工作为胰腺导管腺癌的不同模型系统如何塑造癌细胞的表型空间提供了重要的见解，突出了体内模型的力量。
Intra-tumoral heterogeneity and cellular plasticity have emerged as hallmarks of cancer, including pancreatic ductal adenocarcinoma (PDAC). As PDAC portends a dire prognosis, a better understanding of the mechanisms underpinning cellular diversity in PDAC is crucial. Here, we investigated the cellular heterogeneity of PDAC cancer cells across a range of in vitro and in vivo growth conditions using single-cell genomics. Heterogeneity contracted significantly in 2D and 3D cell culture models but was restored upon orthotopic transplantation. Orthotopic transplants reproducibly acquired cell states identified in autochthonous PDAC tumors, including a basal state exhibiting co-expression and co-accessibility of epithelial and mesenchymal genes. Lineage-tracing combined with single-cell transcriptomics revealed that basal cells display high plasticity in situ. This work defines the impact of cellular growth conditions on phenotypic diversity and uncovers a highly plastic cell state with the capacity to facilitate state transitions and promote intra-tumoral heterogeneity in PDAC. This work provides important insights into how different model systems of pancreatic ductal adenocarcinoma mold the phenotypic space of cancer cells, highlighting the power of in vivo models.