In patients with pancreatic ductal adenocarcinoma (PDAC), intratumoural and intertumoural heterogeneity increases chemoresistance and mortality rates. However, such morphological and phenotypic diversities are not typically captured by organoid models of PDAC. Here we show that branched organoids embedded in collagen gels can recapitulate the phenotypic landscape seen in murine and human PDAC, that the pronounced molecular and morphological intratumoural and intertumoural heterogeneity of organoids is governed by defined transcriptional programmes (notably, epithelial-to-mesenchymal plasticity), and that different organoid phenotypes represent distinct tumour-cell states with unique biological features in vivo. We also show that phenotype-specific therapeutic vulnerabilities and modes of treatment-induced phenotype reprogramming can be captured in phenotypic heterogeneity maps. Our methodology and analyses of tumour-cell heterogeneity in PDAC may guide the development of phenotype-targeted treatment strategies.

在胰腺导管腺癌 （PDAC） 患者中，瘤内和瘤间异质性会增加化疗耐药率和死亡率。然而，这种形态学和表型多样性通常不会被 PDAC 的类器官模型捕获。在这里，我们表明，嵌入胶原凝胶中的分支类器官可以概括在小鼠和人类 PDAC 中看到的表型景观，类器官的显着分子和形态学肿瘤内和肿瘤间异质性受定义的转录程序控制（值得注意的是，上皮到间充质可塑性），并且不同的类器官表型代表不同的肿瘤细胞状态，在体内具有独特的生物学特征。我们还表明，表型特异性治疗脆弱性和治疗诱导的表型重编程模式可以在表型异质性图中捕获。我们对 PDAC 中肿瘤细胞异质性的方法和分析可能指导表型靶向治疗策略的开发。