Pancreatic ductal adenocarcinoma (PDAC) shows pronounced epithelial and mesenchymal cancer cell populations^1,2,3,4. Cellular heterogeneity in PDAC is an important feature in disease subtype specification^3,4,5, but how distinct PDAC subpopulations interact, and the molecular mechanisms that underlie PDAC cell fate decisions, are incompletely understood. Here we identify the BMP inhibitor GREM1^6,7 as a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse. Grem1 inactivation in established PDAC in mice resulted in a direct conversion of epithelial into mesenchymal PDAC cells within days, suggesting that persistent GREM1 activity is required to maintain the epithelial PDAC subpopulations. By contrast, Grem1 overexpression caused an almost complete ‘epithelialization’ of highly mesenchymal PDAC, indicating that high GREM1 activity is sufficient to revert the mesenchymal fate of PDAC cells. Mechanistically, Grem1 was highly expressed in mesenchymal PDAC cells and inhibited the expression of the epithelial–mesenchymal transition transcription factors Snai1 (also known as Snail) and Snai2 (also known as Slug) in the epithelial cell compartment, therefore restricting epithelial–mesenchymal plasticity. Thus, constant suppression of BMP activity is essential to maintain epithelial PDAC cells, indicating that the maintenance of the cellular heterogeneity of pancreatic cancer requires continuous paracrine signalling elicited by a single soluble factor.

胰腺导管腺癌 (PDAC) 显示明显的上皮和间充质癌细胞群^1,2,3,4。^{PDAC 中的细胞异质性是疾病亚型规范3,4,5}中的一个重要特征，但不同的 PDAC 亚群如何相互作用，以及决定 PDAC 细胞命运的分子机制尚不完全清楚。在这里，我们将 BMP 抑制剂 GREM1 ^6,7鉴定为人类和小鼠胰腺癌细胞异质性的关键调节因子。小鼠已建立的 PDAC 中的Grem1失活导致上皮细胞在数天内直接转化为间充质 PDAC 细胞，这表明维持上皮 PDAC 亚群需要持续的 GREM1 活性。相比之下，Grem1过表达导致高度间充质 PDAC 几乎完全“上皮化”，表明高 GREM1 活性足以恢复 PDAC 细胞的间充质命运。从机制上讲，Grem1在间充质 PDAC 细胞中高表达，并抑制上皮-间质转化转录因子Snai1（也称为Snail）和Snai2（也称为Slug ）的表达) 在上皮细胞区室中，因此限制了上皮-间充质的可塑性。因此，持续抑制 BMP 活性对于维持上皮 PDAC 细胞至关重要，表明维持胰腺癌的细胞异质性需要由单一可溶性因子引发的连续旁分泌信号。