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

Benoît Thibault ,Marie Tosolini,Silvia Arcucci,Dina Ferreira Da Mota,Coralie Cayron,Delphine Pagan,Barbara Bournet,Justine Bertrand‐Michel,Alice Carrier,Chiara Falcomatà,Dieter Saur,Romain Baer,Pierre Cordelier,Elvire Pons‐Tostivint,Fabrice Muscari,Nicole Therville,Hongkai Yan,Ezra Aksoy,Fernanda Ramos-Delgado ,A Villard ,Céline Basset ,Jean Pierre Delord ,Célia Cintas ,Gabriela Reyes-Castellanos ,Stéphanie Cassant-Sourdy ,Julie Guillermet-Guibert

doi:10.15252/emmm.202013502

Abstract

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.

Highlights

In humans, PI3Ks are composed of 8 isoforms distributed into 3 classes
We analysed publicly available data set to distinguish a normal pancreas from chronic pancreatitis (CP) and primary tumours from localised Pancreatic ductal adenocarcinoma (PDAC) (PDACloc) or metastatic PDAC (PDACmet) (Fig 1A– C, Dataset EV1)
This trend was confirmed following Reactome pathway analysis; we found that PI3K cascade to FGFR2 was significantly increased in PDACmet as opposed to PDACloc, suggesting differential activation of receptor tyrosine kinase (RTK)-coupled PI3K in these samples

Summary

Introduction

PI3Ks are composed of 8 isoforms distributed into 3 classes. Each class I PI3K dimers, namely called PI3Ka, PI3Kb, PI3Kc and PI3Kd, are composed of a catalytic subunit (p110a, p110b, p110c and p110d) and a regulatory subunit (p85 for a, b and c, and p101/p87 for c). PI3Kc and PI3Kd are restricted to the cardiovascular system and leucocytes in normal tissues, but can be overexpressed in solid tumours (Vanhaesebroeck et al, 2010). PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5–biphosphate (PIP2) into PIP3 which acts as a second messenger and regulates various functions in normal and tumour cells via the PI3K/Akt/ mTOR pathway. The PI3K/Akt axis is frequently hyper-activated in cancers and has been tested as a clinical target in recent years (Pons-Tostivint et al, 2017; Goncalves et al, 2018).

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