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

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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.

Abstract

Signaling by the transforming growth factor–β (TGF-β) receptors I and II (TβRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ceramide metabolism inhibited TβRI/II trafficking to primary cilia to attenuate cross-talk between TβRI/II and the Shh pathway. We found that ceramide synthase 4 (CerS4)–generated ceramide stabilized the association between TβRI and the inhibitory factor Smad7, which limited the trafficking of TβRI/II to primary cilia. Expression of a mutant TβRI that signals but does not interact with Smad7 prevented the CerS4-mediated inhibition of migration in various cancer cells. Genetic deletion or knockdown of CerS4 prevented the formation of the Smad7-TβRI inhibitory complex and increased the association between TβRI and the transporter Arl6 through a previously unknown cilia-targeting signal (Ala31Thr32Ala33Leu34Gln35) in TβRI. Mutating the cilia-targeting signal abolished the trafficking of TβRI to the primary cilia. Localization of TβRI to primary cilia activated a key mediator of Shh signaling, Smoothened (Smo), which stimulated cellular migration and invasion. TβRI-Smo cross-talk at the cilia in CerS4-deficient 4T1 mammary cancer cells induced liver metastasis from orthotopic allografts in both wild-type and CerS4-deficient mice, which was prevented by overexpression of Smad7 or knockdown of intraflagellar transport protein 88 (IFT88). Overall, these data reveal a ceramide-dependent mechanism that suppresses cell migration and invasion by restricting TβRI/II-Shh signaling selectively at the plasma membrane of the primary cilium.

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