Kras-activating mutations display the highest incidence in pancreatic ductal adenocarcinoma. Pancreatic inflammation accelerates mutant Kras-driven tumorigenesis in mice, suggesting high selectivity in the cells that oncogenic Kras transforms, although the mechanisms dictating this specificity are poorly understood. Here we show that pancreatic inflammation is coupled to the emergence of a transient progenitor cell population that is readily transformed in the presence of mutant KrasG12D. These progenitors harbor a proto-oncogenic transcriptional program driven by a transient enhancer network. KrasG12D mutations lock this enhancer network in place, providing a sustained Kras-dependent oncogenic program that drives tumors throughout progression. Enhancer co-option occurs through functional interactions between the Kras-activated transcription factors Junb and Fosl1 and pancreatic lineage transcription factors, potentially accounting for inter-tissue specificity of oncogene transformation. The pancreatic ductal adenocarcinoma cell of origin thus provides an oncogenic transcriptional program that fuels tumor progression beyond initiation, accounting for the intra-tissue selectivity of Kras transformation.

Kras 激活突变在胰腺导管腺癌中的发病率最高。胰腺炎症加速了小鼠中突变的 Kras 驱动的肿瘤发生，表明致癌 Kras 转化的细胞具有高选择性，尽管对这种特异性的机制知之甚少。在这里，我们表明胰腺炎症与瞬时祖细胞群的出现有关，该祖细胞群在突变 KrasG12D 存在下很容易转化。这些祖细胞具有由瞬时增强子网络驱动的原癌基因转录程序。KrasG12D 突变将这个增强子网络锁定在适当的位置，提供持续的 Kras 依赖性致癌程序，在整个进展过程中驱动肿瘤。增强子共同选择通过 Kras 激活的转录因子 Junb 和 Fosl1 与胰腺谱系转录因子之间的功能相互作用发生，这可能解释了癌基因转化的组织间特异性。因此，起源的胰腺导管腺癌细胞提供了一种致癌转录程序，该程序促进了肿瘤在起始后的进展，解释了 Kras 转化的组织内选择性。