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.

中文翻译：

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胰腺导管腺癌模型的系统比较确定了保守的高度可塑性基底细胞状态


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，因此更好地了解 PDAC 细胞多样性的机制至关重要。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。异质性在 2D 和 3D 细胞培养模型中显着收缩，但在原位移植后恢复。原位移植可重复获得在本地 PDAC 肿瘤中鉴定的细胞状态，包括表现出上皮和间质基因共表达和共可及性的基础状态。谱系追踪与单细胞转录组学相结合揭示基底细胞在原位表现出高可塑性。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的细胞状态，具有促进状态转换和促进 PDAC 肿瘤内异质性的能力。