Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the produced lipid second messenger PIP₃, with a selective decrease of C36:2 PI-3,4,5-P₃. Tumoural PI3Kα inactivation prevented the accumulation of pro-tumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Kα promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution.

中文翻译：

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胰腺癌内在的 PI3Kα 活性加速转移并重新连接巨噬细胞成分

胰腺导管腺癌（PDAC）患者经常患有未被发现的微转移性疾病。这种临床情况将大大受益于额外的调查。因此，我们着手确定驱动胰腺转移进化的关键信号事件。我们搜索了区分局部 PDAC 和确诊转移性 PDAC 的基因特征，并设计了一种临床前方案，使用循环游离 DNA (cfDNA) 作为微转移性疾病的早期生物标志物，以验证关键信号事件的识别。一种公正的方法在疾病进展的可行标志物中确定了 PI3K 通路和独特的 PI3Kα 激活特征，可预测 PDAC 的侵袭性和预后。药理学或肿瘤限制性遗传 PI3Kα 选择性抑制通过阻碍肿瘤细胞的独立于遗传改变的迁移行为来阻止宏观转移进化。_{我们发现，PI3Kα 抑制改变了产生的脂质第二信使 PIP 3}的数量和种类组成，选择性减少了 C36:2 PI-3,4,5-P ₃。肿瘤 PI3Kα 失活阻止了促肿瘤 CD206 阳性巨噬细胞在肿瘤邻近组织中的积累。肿瘤细胞固有的 PI3Kα 促进促转移特征，这些特征可以在药理学上靶向延迟宏观转移的进化。