Dynamic Regulation of Expression of KRAS and Its Effectors Determines the Ability to Initiate Tumorigenesis in Pancreatic Acinar Cells
Dynamic Regulation of Expression of KRAS and Its Effectors Determines the Ability to Initiate Tumorigenesis in Pancreatic Acinar Cells
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DOI：
10.1158/0008-5472.can-20-2976
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发表时间：
2021-05-15
期刊：
影响因子：
11.2
通讯作者：
Jacquemin, Patrick
中科院分区：
文献类型：
--
作者：
Assi, Mohamad;Achouri, Younes;Jacquemin, Patrick
胰腺腺泡细胞是胰腺癌的一种细胞来源，出生后对致癌Kras突变诱导的肿瘤发生逐渐不敏感。当Kras突变合并胰腺炎时，这种敏感性增加。这些观察结果背后的分子机制在很大程度上仍然未知。为了确定这些机制，我们创建了第一个crispr编辑的小鼠模型，能够在体内检测野生型和突变型KRAS蛋白。对这些小鼠模型的分析显示，超过75%的成年腺泡细胞缺乏可检测到的KRAS蛋白。在25%的表达KRAS蛋白的腺泡细胞中，转录组学分析强调了RAS和MAPK通路的轻微上调。然而，在蛋白水平上，仅观察到必要的KRAS效应物（包括C-RAF）在胰腺的边缘表达。KRAS及其效应因子的表达在出生后逐渐降低。成人腺泡细胞对Kras突变的低敏感性是由于Kras及其效应物的低表达以及随后RAS/MAPK通路的缺乏激活。胰腺炎触发KRAS及其效应物的表达以及随后下游信号的激活；这种诱导需要EGFR的活性。最后，C-RAF在成人胰腺中的表达是胰腺肿瘤发生所必需的。总之，我们的研究表明，控制KRAS及其效应物的表达可调节腺泡细胞对致癌KRAS突变转化的敏感性。意义：本研究建立了新的小鼠模型来研究KRAS在胰腺肿瘤发生过程中的调控，并揭示了胰腺炎使腺泡细胞对KRAS突变致敏的新机制。
Pancreatic acinar cells are a cell type of origin for pancreatic cancer that become progressively less sensitive to tumorigenesis induced by oncogenic Kras mutations after birth. This sensitivity is increased when Kras mutations are combined with pancreatitis. Molecular mechanisms underlying these observations are still largely unknown. To identify these mechanisms, we generated the first CRISPR-edited mouse models that enable detection of wild-type and mutant KRAS proteins in vivo. Analysis of these mouse models revealed that more than 75% of adult acinar cells are devoid of detectable KRAS protein. In the 25% of acinar cells expressing KRAS protein, transcriptomic analysis highlighted a slight upregulation of the RAS and MAPK pathways. However, at the protein level, only marginal pancreatic expression of essential KRAS effectors, including C-RAF, was observed. The expression of KRAS and its effectors gradually decreased after birth. The low sensitivity of adult acinar cells to Kras mutations resulted from low expression of KRAS and its effectors and the subsequent lack of activation of RAS/MAPK pathways. Pancreatitis triggered expression of KRAS and its effectors as well as subsequent activation of downstream signaling; this induction required the activity of EGFR. Finally, expression of C-RAF in adult pancreas was required for pancreatic tumorigenesis. In conclusion, our study reveals that control of the expression of KRAS and its effectors regulates the sensitivity of acinar cells to transformation by oncogenic Kras mutations.Significance: This study generates new mouse models to study regulation of KRAS during pancreatic tumorigenesis and highlights a novel mechanism through which pancreatitis sensitizes acinar cells to Kras mutations.