Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high-grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear. Here, we aimed to identify how PDAC cells instruct the main cellular component of stroma, the pancreatic stellate cells (PSCs). We found in primary tissue that high-grade PDAC had reduced collagen deposition compared to low-grade PDAC. Xenografts and organotypic co-cultures established from mesenchymal-like PDAC cells featured reduced collagen and activated PSC content. Medium transfer experiments using a large set of PDAC cell lines revealed that mesenchymal-like PDAC cells consistently downregulated ACTA2 and COL1A1 expression in PSCs and reduced proliferation. We identified colony-stimulating factor 1 as the mesenchymal PDAC-derived ligand that deactivates PSCs, and inhibition of its receptor CSF1R was able to counteract this effect. In conclusion, high-grade PDAC features stroma that is low in collagen and activated PSC content, and targeting CSF1R offers direct options to maintain a tumor-restricting microenvironment.

中文翻译：

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高级别间充质胰腺导管腺癌通过 CSF-1 驱动基质失活。

胰腺导管腺癌（PDAC）的特点是基质丰富。多种分子分类工作已经确定了一种间充质肿瘤亚型，其一贯的特点是高级别生长和不良的临床结果。PDAC 基质与肿瘤亚型之间的关系仍不清楚。在这里，我们的目的是确定 PDAC 细胞如何指导基质的主要细胞成分——胰腺星状细胞 (PSC)。我们发现在原代组织中，与低等级 PDAC 相比，高等级 PDAC 减少了胶原蛋白沉积。由间充质样 PDAC 细胞建立的异种移植物和器官共培养物具有胶原蛋白和活化 PSC 含量减少的特点。使用大量 PDAC 细胞系的培养基转移实验表明，间充质样 PDAC 细胞持续下调 PSC 中的 ACTA2 和 COL1A1 表达并减少增殖。我们确定集落刺激因子 1 是间充质 PDAC 衍生的配体，可以使 PSC 失活，抑制其受体 CSF1R 能够抵消这种作用。总之，高级 PDAC 的基质胶原蛋白和活化 PSC 含量较低，靶向 CSF1R 提供了维持肿瘤限制微环境的直接选择。