Background & Aims

Acinar to ductal metaplasia is the prerequisite for the initiation of Kras-driven pancreatic ductal adenocarcinoma (PDAC), and candidate genes regulating this process are emerging from genome-wide association studies. The adaptor protein p130Cas emerged as a potential PDAC susceptibility gene and a Kras-synthetic lethal interactor in pancreatic cell lines; however, its role in PDAC development has remained largely unknown.

Methods

Human PDAC samples and murine Kras^G12D-dependent pancreatic cancer models of increasing aggressiveness were used. p130Cas was conditionally ablated in pancreatic cancer models to investigate its role during Kras-induced tumorigenesis.

Results

We found that high expression of p130Cas is frequently detected in PDAC and correlates with higher histologic grade and poor prognosis. In a model of Kras-driven PDAC, loss of p130Cas inhibits tumor development and potently extends median survival. Deletion of p130Cas suppresses acinar-derived tumorigenesis and progression by means of repressing PI3K–AKT signaling, even in the presence of a worsening condition like pancreatitis.

Conclusions

Our observations finally demonstrated that p130Cas acts downstream of Kras to boost the PI3K activity required for acinar to ductal metaplasia and subsequent tumor initiation. This demonstrates an unexpected driving role of p130Cas downstream of Kras through PI3K/AKT, thus indicating a rational therapeutic strategy of targeting the PI3K pathway in tumors with high expression of p130Cas.

中文翻译：

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对接蛋白 p130Cas 在胰腺腺癌发展和胰腺炎期间调节腺泡到导管化生

背景与目标

腺泡到导管化生是 Kras 驱动的胰腺导管腺癌 (PDAC) 发生的先决条件，调节这一过程的候选基因正在从全基因组关联研究中出现。衔接蛋白 p130Cas 成为胰腺细胞系中潜在的 PDAC 易感基因和 Kras 合成的致死相互作用物；然而，它在 PDAC 开发中的作用在很大程度上仍然未知。

方法

使用了侵袭性增加的人类 PDAC 样品和鼠 Kras ^G12D依赖性胰腺癌模型。p130Cas 在胰腺癌模型中被有条件地消融，以研究其在 Kras 诱导的肿瘤发生中的作用。

结果

我们发现在 PDAC 中经常检测到 p130Cas 的高表达，并且与较高的组织学分级和较差的预后相关。在 Kras 驱动的 PDAC 模型中，p130Cas 的缺失抑制了肿瘤的发展并有效地延长了中位生存期。p130Cas 的缺失通过抑制 PI3K-AKT 信号传导来抑制腺泡衍生的肿瘤发生和进展，即使在胰腺炎等病情恶化的情况下也是如此。

结论

我们的观察最终表明，p130Cas 在 Kras 的下游作用以增强腺泡到导管化生和随后的肿瘤发生所需的 PI3K 活性。这证明了 p130Cas 通过 PI3K/AKT 在 Kras 下游的意外驱动作用，从而表明在 p130Cas 高表达的肿瘤中靶向 PI3K 通路的合理治疗策略。