Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells.
Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells.
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DOI：
10.1038/onc.2015.437
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发表时间：
2016-07-21
期刊：
影响因子：
8
通讯作者：
Schneider G
中科院分区：
文献类型：
--
作者：
Diersch S;Wirth M;Schneeweis C;Jörs S;Geisler F;Siveke JT;Rad R;Schmid RM;Saur D;Rustgi AK;Reichert M;Schneider G
表皮生长因子受体（EGFR）信号转导在致癌Kras驱动的胰腺癌发生中具有关键作用。然而，这个信令网络的下游目标在很大程度上是未知的。我们开发了一种新的模型系统，利用小鼠原代胰腺导管上皮细胞（PDEC），基因工程，允许时间特异性表达致癌KrasG 12 D从内源性启动子。我们发现，原发性PDEC对KrasG 12 D驱动的转化敏感，并在Cdkn 2a失活后在体内形成胰腺导管腺癌（PDAC）。此外，我们证明了KrasG 12 D的激活诱导EGFR信号环来驱动增殖。有趣的是，EGFR的药理学抑制未能降低KrasG 12 D激活的ERK或PI 3 K信号传导。相反，我们的数据提供了新的证据，EGFR信号需要激活致癌和促增殖转录因子c-MYC。EGFR和c-MYC已被证明是胰腺癌发生所必需的。重要的是，我们的数据将这两种途径联系起来，从而解释了EGFR在胰腺中KrasG 12 D驱动的致癌作用中的关键作用。
Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic KrasG12D from the endogenous promoter. We show that primary PDECs are susceptible to KrasG12D-driven transformation and form pancreatic ductal adenocarcinomas (PDAC) in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of KrasG12D induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease KrasG12D-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby, explain the crucial role of EGFR for KrasG12D-driven carcinogenesis in the pancreas.