Research ArticleCancer

TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis

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Sci. Signal.  24 Oct 2017:
Vol. 10, Issue 502, eaam7464
DOI: 10.1126/scisignal.aam7464

The good side of ceramides

Ceramides are lipids that contribute to various cellular structures and functions. In the context of cancer, some ceramides, and the enzymes that produce them, contribute to tumor growth because they provide a critical component of the plasma membrane, enabling cells to divide. However, Gencer et al. found that certain long-chain ceramides synthesized by the enzyme CerS4 play a critical tumor suppressor role. C18- to C20-ceramides mediated the interaction between an inhibitory Smad protein and a TGF-β receptor complex, thus blocking subsequent cross-talk activation of the sonic hedgehog (Shh) pathway in tumor cells’ primary cilia, a region of the cell that coordinates motility. Depleting CerS4 in tumor cells increased the incidence of distant metastases from mammary tumors in mice. The disruption of TGF-β–Shh cross-talk by CerS4 may also prevent the development of the hair loss disorder alopecia. Both the TGF-β and Shh pathways are challenging to target pharmacologically; these findings suggest that some ceramides may have therapeutic potential against these pathways in various disorders.