Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component

• Published in: EMBO molecular medicine Vol. 13; no. 7; pp. e13502 - n/a
• Main Authors: Thibault, Benoit, Ramos‐Delgado, Fernanda, Pons‐Tostivint, Elvire, Therville, Nicole, Cintas, Celia, Arcucci, Silvia, Cassant‐Sourdy, Stephanie, Reyes‐Castellanos, Gabriela, Tosolini, Marie, Villard, Amelie V, Cayron, Coralie, Baer, Romain, Bertrand‐Michel, Justine, Pagan, Delphine, Ferreira Da Mota, Dina, Yan, Hongkai, Falcomatà, Chiara, Muscari, Fabrice, Bournet, Barbara, Delord, Jean‐Pierre, Aksoy, Ezra, Carrier, Alice, Cordelier, Pierre, Saur, Dieter, Basset, Celine, Guillermet‐Guibert, Julie
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 07.07.2021; John Wiley & Sons, Inc; EMBO Press; Wiley Open Access; Wiley-Blackwell; John Wiley and Sons Inc; Springer Nature
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; Biochemistry, Molecular Biology; Biomarkers; Cancer; Carcinoma, Pancreatic Ductal - genetics; Cell migration; Datasets; Development and progression; EMBO03; EMBO37; Evolution; Gene expression; Genomics; Human health and pathology; Human health sciences; Humans; Hépatology and Gastroenterology; Kinases; Life Sciences; Macrophages; Medical prognosis; Metastases; Metastasis; Muscle proteins; Mutation; Oncologie; Oncology; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatitis; Patients; Phosphatidylinositol 3,4,5-triphosphate; Phosphatidylinositol 3-Kinases - genetics; phosphoinositide; PI3K isoforms; Prognosis; Sciences de la santé humaine; Signal transduction; Species composition; targeted therapy; Tumors; tumour‐stroma dialog; targeted therapy; pancreatic cancer; PI3K isoforms; phosphoinositide; tumour‐stroma dialog; tumour-stroma dialog; Signal Transduction; Pancreatic cancer; tumour-stroma dialog Subject Categories Cancer
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.202013502

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 PIP 3 , with a selective decrease of C36:2 PI‐3,4,5‐P 3 . 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. SYNOPSIS Primary tumours from metastatic PDAC patients are characterized by a selective transcriptomics signature, including a gene signature representative of PI3Kα activation, which predicts tumour evolution. PDAC tumour cell migration is regulated by a minimal PI3Kα activity. PI3Kα tumour cell intrinsic activity is triggered by oncogenic mutations and by a tumoural context such as secreted FGF receptor ligands. Macrophage TNFα secretion is promoted by PI3Kα activity‐induced IL‐3 in tumour cell; conversely, tumour cell migration is promoted by TNFα. Higher level of cfDNA with KRAS mutation in pancreatic cancer patients is associated with increased PI3K activity markers in primary tumour. Evolution from micro‐metastatic disease to macro‐metastatic stage is dependent on PI3Kα activity and is prevented by PI3Kα pharmacological inhibition. Graphical Abstract Primary tumours from metastatic PDAC patients are characterized by a selective transcriptomics signature, including a gene signature representative of PI3Kα activation, which predicts tumour evolution.