CD95L cell surface cleavage triggers a prometastatic signaling pathway in triple-negative breast cancer.
Triple-negative breast cancers (TNBC) lacking estrogen and progesterone receptors and HER2 amplification have a relatively high risk of metastatic dissemination, but the mechanistic basis for this risk is not understood. Here, we report that serum levels of CD95 ligand (CD95L) are higher in patients with TNBC than in other patients with breast cancer. Metalloprotease-mediated cleavage of CD95L expressed by endothelial cells surrounding tumors generates a gradient that promotes cell motility due to the formation of an unconventional CD95-containing receptosome called the motility-inducing signaling complex. The formation of this complex was instrumental for Nox3-driven reactive oxygen species generation. Mechanistic investigations revealed a Yes-Orai1-EGFR-PI3K pathway that triggered migration of TNBC cells exposed to CD95L. Our findings establish a prometastatic function for metalloprotease-cleaved CD95L in TNBCs, revisiting its role in carcinogenesis.
Authors' Affiliations: Inserm U1085-IRSET, Equipe Labellisée Ligue Contre Le Cancer; Université de Rennes-1; Centre Eugène Marquis, rue bataille Flandres Dunkerque, Rennes; ImmuSmol, 15 Rue Amiral Prouhet, Pessac; Inserm, U1068; Institut Paoli-Calmettes; Aix-Marseille Université, CNRS, UMR 7258, Marseille; ICO-René Gauducheau, Bd J. Monod, Saint-Herblain; Université de Bordeaux; Inserm U1045, Université Bordeaux Segalen; and Inserm U916, Institut Bergonié, Bordeaux, France.
Marine
M
Malleter
Sébastien
S
Tauzin
Alban
A
Bessede
Rémy
R
Castellano
Armelle
A
Goubard
Florence
F
Godey
Jean
J
Levêque
Pascal
P
Jézéquel
Loic
L
Campion
Mario
M
Campone
Thomas
T
Ducret
Gaëtan
G
MacGrogan
Laure
L
Debure
Yves
Y
Collette
Pierre
P
Vacher
Patrick
P
Legembre
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002465:Cell Movement; D053222:Fas Ligand Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D053222:Fas Ligand Protein; D017382:Reactive Oxygen Species