Background & Aims

Although the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as pancreatic intraepithelial neoplasia, are characterized by an extensive accumulation of fibroinflammatory stroma that includes a substantial and heterogeneous fibroblast population. The cellular origin of fibroblasts within the stroma has not been determined. Here, we show that the Gli1 and Hoxb6 markers label distinct fibroblast populations in the healthy mouse pancreas. We then set out to determine whether these distinct fibroblast populations expanded during carcinogenesis.

Methods

We developed genetically engineered models using a dual-recombinase approach that allowed us to induce pancreatic cancer formation through codon-optimized Flp recombinase-driven epithelial recombination of Kirsten rat sarcoma viral oncogene homolog while labeling Gli1⁺ or Hoxb6⁺ fibroblasts in an inducible manner. By using these models, we lineage-traced these 2 fibroblast populations during the process of carcinogenesis.

Results

Although in the healthy pancreas Gli1⁺ fibroblasts and Hoxb6⁺ fibroblasts are present in similar numbers, they contribute differently to the stroma in carcinogenesis. Namely, Gli1⁺ fibroblasts expand dramatically, whereas Hoxb6⁺ cells do not.

Conclusions

Fibroblasts present in the healthy pancreas expand during carcinogenesis, but with a different prevalence for different subtypes. Here, we compared Gli1⁺ and Hoxb6⁺ fibroblasts and found only Gli1⁺ expanded to contribute to the stroma during pancreatic carcinogenesis.

中文翻译：

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胰腺成纤维细胞亚群对胰腺癌基质的不同贡献。

背景与目标

尽管健康的胰腺主要由上皮细胞组成，但胰腺癌和称为胰腺上皮内瘤变的前体病变的特征在于纤维炎症基质的广泛积累，其中包括大量和异质的成纤维细胞群。尚未确定基质内成纤维细胞的细胞来源。在这里，我们显示 Gli1 和 Hoxb6 标记标记健康小鼠胰腺中不同的成纤维细胞群。然后，我们着手确定这些不同的成纤维细胞群是否在癌变过程中扩大。

方法

我们使用双重组酶方法开发了基因工程模型，这使我们能够通过密码子优化的 Flp 重组酶驱动的 Kirsten 大鼠肉瘤病毒癌基因同源物的上皮重组，同时以可诱导的方式标记 Gli1 ⁺或 Hoxb6 ⁺成纤维细胞来诱导胰腺癌的形成。通过使用这些模型，我们在癌变过程中对这 2 个成纤维细胞群进行了谱系追踪。

结果

尽管在健康的胰腺中 Gli1 ⁺成纤维细胞和 Hoxb6 ⁺成纤维细胞的数量相似，但它们对基质的致癌作用不同。也就是说，Gli1 ⁺成纤维细胞急剧扩张，而 Hoxb6 ⁺细胞则没有。

结论

健康胰腺中存在的成纤维细胞在癌变过程中会扩张，但不同亚型的患病率不同。在这里，我们比较了 Gli1 ⁺和 Hoxb6 ⁺成纤维细胞，发现只有 Gli1 ⁺在胰腺癌发生过程中对基质起作用。