TY - JOUR
T1 - Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component
AU - Thibault, Benoit
AU - Ramos-Delgado, Fernanda
AU - Pons-Tostivint, Elvire
AU - Therville, Nicole
AU - Cintas, Celia
AU - Arcucci, Silvia
AU - Cassant-Sourdy, Stephanie
AU - Reyes-Castellanos, Gabriela
AU - Tosolini, Marie
AU - Villard, Amelie V.
AU - Cayron, Coralie
AU - Baer, Romain
AU - Bertrand-Michel, Justine
AU - Pagan, Delphine
AU - Ferreira Da Mota, Dina
AU - Yan, Hongkai
AU - Falcomatà, Chiara
AU - Muscari, Fabrice
AU - Bournet, Barbara
AU - Delord, Jean Pierre
AU - Aksoy, Ezra
AU - Carrier, Alice
AU - Cordelier, Pierre
AU - Saur, Dieter
AU - Basset, Celine
AU - Guillermet-Guibert, Julie
N1 - Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2021/7/7
Y1 - 2021/7/7
N2 - 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.
AB - 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.
KW - PI3K isoforms
KW - pancreatic cancer
KW - phosphoinositide
KW - targeted therapy
KW - tumour-stroma dialog
UR - http://www.scopus.com/inward/record.url?scp=85106270780&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85106270780&partnerID=8YFLogxK
U2 - 10.15252/emmm.202013502
DO - 10.15252/emmm.202013502
M3 - Article
C2 - 34033220
AN - SCOPUS:85106270780
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 7
M1 - e13502
ER -