Abstract 4122: Ceramide is a key factor that regulates the crosstalk between TGF-ß and sonic hedgehog signaling at the basal cilia to control cell migration and tumor metastasis

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Recent studies indicate that ceramide species with different fatty-acid chain lengths play diverse biological functions in various cellular processes, highlighting the importance of ceramide synthases (CerS) in these processes. Migration and cell mobility, a part of these processes, also are effected by ceramide metabolism. However, the molecular mechanism of CerS/and ceramide involved is unknown. Here, we investigated the effect of CerS/and ceramide on migration and its related signal pathways in situ and in vivo model. Interestingly, our data show that among CerS only CerS4/ceramide is involved to cell migration and tumor metastasis. Here, we also have generated CerS4-/- mice for in vivo studies. Interestingly, we observed that genetically loss of CerS4 resulted in severe irreversible alopecia, which was associated with hyper-proliferation and migration of keratinocytes. Mechanistically, we show here that genetic loss or shRNA-mediated knockdown of CerS4 enhances cell migration by which ligand-independent signaling of TGF-beta receptors I and II in various cell types, including keratinocytes, mouse embryonic fibroblasts and cancer cells. Moreover, we found that ceramide directly interact with Smad7 and this interaction was decreased by shRNA-mediated knockdown of CerS4. Thus, ceramide-Smad7 binding modulates plasma membrane association of TGF-sR1 at primary basal cilia, and inhibits its signaling through Sonic-Hedgehog (Shh) for migration. Furthermore, Ceramide accumulation at the primary basal cilia was decreased by knockdown of CerS4. Thus, these data revealed that CerS4/ceramide signaling plays key roles in the regulation of cell migration and metastasis via controlling the TGF-sR and Shh axis at primary basal cilia. Citation Format: Salih Gencer, Natalia Oleinik, Mohammed Dany, Besim Ogretmen. Ceramide is a key factor that regulates the crosstalk between TGF-s and sonic hedgehog signaling at the basal cilia to control cell migration and tumor metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4122.