ProNGF increases breast tumor aggressiveness through functional association of TrkA with EphA2

Romain Lévêque (1, 2) , Cyril Corbet (1, 2) , Léo Aubert (1, 2) , Matthieu Guilbert (1, 2) , Chann Lagadec (1, 2) , Eric Adriaenssens (1, 2) , Jérémy Duval (1, 2) , Pascal Finetti (3) , Daniel Birnbaum (3) , Nicolas Magné (1, 2, 4) , Valérie Chopin (1, 2, 5) , François Bertucci (1, 2, 3) , Xuefen Le Bourhis (1, 2) , Robert-Alain Toillon (1, 2)

1 CPAC - Plasticité Cellulaire et Cancer - U908
2 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
3 CRCM - Centre de Recherche en Cancérologie de Marseille
4 Institut de Cancérologie Lucien Neuwirth
5 UPJV - Université de Picardie Jules Verne

ProNGF expression has been linked to several types of cancers including breast cancer, and we have previously shown that proNGF stimulates breast cancer invasion in an autocrine manner through membrane receptors sortilin and TrkA. However, little is known regarding TrkA-associated protein partners upon proNGF stimulation. By proteomic analysis and proximity ligation assays, we found that proNGF binding to sortilin induced sequential formation of the functional sortilin/TrkA/EphA2 complex, leading to TrkA-phosphorylation dependent Akt activation and EphA2-dependent Src activation. EphA2 inhibition using siRNA approach abolished proNGF-stimulated clonogenic growth of breast cancer cell lines. Combinatorial targeting of TrkA and EphA2 dramatically reduced colony formation in vitro, primary tumor growth and metastatic dissemination towards the brain in vivo. Finally, proximity ligation assay in breast tumor samples revealed that increased TrkA/EphA2 proximity ligation assay signals were correlated with a decrease of overall survival in patients. All together, these data point out the importance of TrkA/EphA2 functional association in proNGF-induced tumor promoting effects, and provide a rationale to target proNGF/TrkA/EphA2 axis by alternative methods other than the simple use of tyrosine kinase inhibitors in breast cancer.

Mots clés: EphA2; TrkA; proNGF; Breast cancer

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Romain Lévêque, Cyril Corbet, Léo Aubert, Matthieu Guilbert, Chann Lagadec, et al.. ProNGF increases breast tumor aggressiveness through functional association of TrkA with EphA2. Cancer Letters, 2019, 449, pp.196 - 206. ⟨10.1016/j.canlet.2019.02.019⟩. ⟨hal-04276997v2⟩