Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.

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