Pancreatic Cancer Intrinsic PI3Kα Activity accelerates Metastasis and rewires Macrophage Component
Authors: Thibault B. , Ramos Delgado F. , Pons-Tostivint E. , Therville N. , Cintas C. , Arcucci S. , Cassant-Sourdy S. , Reyes-Castellanos G. , Tosolini M. , Villard A.V. , Cayron C. , Baer R. , Bertrand-Michel J. , Payen D. , Yan H. , Falcomata C. , Muscari F. , Bournet B. , Delord JP. , Aksoy E. , Carrier A. , Cordelier P. , Saur D. , Basset C. , Guillermet-Guibert J. 
Published: September 2020

AbstractPancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micrometastatic 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 researched a gene signature that could 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.Amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature predict PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by inhibiting tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the lipid second messenger PIP3produced, with selective reduction of C36:2 PI-3,4,5-P3. PI3Kα inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue.Tumour-cell intrinsic PI3Kα therefore promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution.The paper explainedPROBLEM Pancreatic cancer is one of the most lethal solid cancers characterised by rapid progression after primary tumour detection by imaging. Key signalling events that specifically drives this rapid evolution into macro-metastatic disease are so far poorly understood.RESULT With two unbiased approaches to patient data analysis, higher PI3K pathway and more specifically higher PI3Kα activation signature can now be identified in the most aggressive pancreatic cancer primary tumours, that lead to earlier patient death. Our in vitro data showed that PI3Kα is a major positive regulator of tumour cell escape from the primary tumour: tumour-intrinsic PI3Kα activity enables actin cytoskeleton remodelling to escape the pancreatic tumour. We chose to use two preclinical models of pancreatic cancer to validate that PI3Kα is a target for delaying evolution of PDAC. The first one mimicked pancreatic patient micrometastatic disease that is undetected by echography and consisted in treating mice presenting echography detected primary tumours combined with increased circulating DNA as a blood biomarker of the most aggressive tumours. The second model consisted in studying the tumour cell implantation and their early proliferation in metastatic organ after injection in blood. We treated both preclinical models with a clinically relevant PI3K α-selective inhibitor (BYL-719/Alpelisib), that is currently being tested in pancreatic cancer patients (without any patient selection). We found that PI3Kα activity drives evolution of micrometastatic disease towards macro-metastatic stage in both models: inhibition of PI3Kα delayed primary tumour and micro-metastasis evolution. Finally, PI3Kα activity increases protumoural characteristics in peritumoural immune cells via tumour cell-intrinsic cytokine production that could facilitate metastatic evolution.IMPACT Circulating tumour DNA represents a strong independent biomarker linked to relapse and poor survival in solid cancer patients. A clinical study in resected PDAC patients with micrometastatic disease characterised by high circulating tumoural DNA levels is needed to assess if PI3Kα-selective inhibitors significantly delay metastatic progression and death.Graphical AbstractPancreatic ductal adenocarcinoma requires tumour-intrinsic PI3Kα activity to accelerate inflammatory metastatic disease.Biorender illustration.