Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.

胰腺导管腺癌（PDAC）的瘤内形态异质性可预测临床结果，但仅在分子水平上得到部分了解。为了阐明 PDAC 肿瘤内形态变异的基因表达程序，我们在单细胞水平上研究并解卷积了组织学上不同的 PDAC 细胞簇的分子谱。我们确定了三种主要的形态和功能变异，它们以不同比例共存于所有 PDAC 中，显示出有限的遗传多样性，并且与细胞外基质的独特组织相关：具有经典导管特征的腺体变异；显示流产导管结构和混合内胚层和肌成纤维细胞样基因表达的过渡变体；以及缺乏导管特征和基底膜并显示神经元谱系启动的低分化变体。离体和体外证据支持这些变异之间发生动态转变，部分受到细胞外基质组成和硬度的影响，并与局部（特别是神经）侵袭相关。