Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR4-SDF-1α signaling axis.

We previously reported that exosomes secreted by human pancreatic tumor cells induce cell death through the inhibition of the Notch-1 survival pathway (Ristorcelli et al., 2009). We demonstrated that exosomal lipids evoked apoptosis of human pancreatic cancer SOJ-6 cells. Based on the lipid composition of efficient exosomes we designed Synthetic Exosome-Like Nanoparticles (SELN) in which the ratio ordered lipids versus disordered lipids was equal to 6.0 (SELN6.0). These SELN decreased SOJ-6 cells survival by inhibiting the Notch-1 pathway. However MiaPaCa-2 cells were resistant to exosomes (Ristorcelli et al., 2008) and to SELN6.0 (Beloribi et al.,2012). In this paper we aimed at deciphering the reason(s) of this resistance. We observed, in presence of SELN6.0, that the expression of the Notch IntraCytoplasmic Domain (NICD) decreases in MiaPaCa-2 cells but neither Hes-1, the nuclear target of NICD, nor the ratio Bax/Bcl-2 were affected. We further showed that in MiaPaCa-2 cells SELN6.0 induced the activation of NF-kB, which promotes the expression and the secretion of SDF-1α. This chemokine interacts with its receptor CXCR4 on MiaPaCa-2 cells and activates the Akt survival pathway protecting cells from death. This activation process promoted by exosomal lipids could have implications in tumor progression and drug resistance.