Primary cilia can both mediate and suppress Hedgehog pathway–dependent tumorigenesis

Abstract

Primary cilia are present on most mammalian cells and are implicated in transducing Hedgehog (Hh) signals during development; however, the prevalence of cilia on human tumors remains unclear, and the role of cilia in cancer has not been examined. Here we show that human basal cell carcinomas (BCCs) are frequently ciliated, and we test the role of cilia in BCC by conditionally deleting Kif3a (encoding kinesin family member 3A) or Ift88 (encoding intraflagellar transport protein 88), genes required for ciliogenesis, in two Hh pathway–dependent mouse tumor models. Ciliary ablation strongly inhibited BCC-like tumors induced by an activated form of Smoothened. In contrast, removal of cilia accelerated tumors induced by activated Gli2, a transcriptional effector of Hh signaling. These seemingly paradoxical effects are consistent with a dual role for cilia in mediating both the activation and the repression of the Hh signaling pathway. Our findings demonstrate that cilia function as unique signaling organelles that can either mediate or suppress tumorigenesis depending on the nature of the oncogenic initiating event.

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Figure 1: BCC and normal skin cells possess primary cilia.
Figure 2: Cilia are essential for SmoM2-induced neoplasia.
Figure 3: Loss of cilia accelerates GLI2ΔN-induced neoplasia.
Figure 4: Loss of Ift88 restrains SmoM2-mediated tumorigenesis and promotes GLI2ΔN-induced BCC-like lesions in tamoxifen-treated mice.

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Acknowledgements

We thank D. Hanahan, O. Nolan-Stevaux, G. Evan and the members of the Reiter lab for critical reading of this manuscript; K. Thorn and the UCSF Nikon Imaging Center for assistance with confocal microscopy; C. Miller and J.D. Fish for assistance with histology; and R. T. Bronson for help with pathology. We thank T. Li, Harvard Medical School, for rabbit antibody to rootletin; K.V. Anderson, Sloan-Kettering Institute, for Ift172−/− MEFs; S. Scales, Genentech, for mouse antibody to Gli3; J.T. Eggenschwiler, Princeton University, for guinea pig antibody to Gli2; B. Yoder, University of Alabama at Birmingham, for Ift88flox mice; L. Goldstein, University of California, San Diego, for Kif3aflox-knockout mice; and L.V. Goodrich, Harvard Medical School, for Ptch1 riboprobe plasmid. This work was funded by grants from the US National Institutes of Health (RO1AR054396), the Burroughs Wellcome Fund, the Packard Foundation and the Sandler Family Supporting Foundation to J.F.R. A.A.D. acknowledges the support of the US National Institutes of Health (RO1CA087837). S.Y.W. acknowledges the support of the A.P. Giannini Foundation, the Herbert W. Boyer Fund and the American Cancer Society.

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S.Y.W. and J.F.R. designed experiments, performed research, analyzed data and wrote the manuscript. A.D.S. assisted with mouse experiments. P.-L.S., A.N.E., C.K.B., E.H.E. and A.A.D. provided reagents and technical advice.

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Correspondence to Jeremy F Reiter.

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Wong, S., Seol, A., So, P. et al. Primary cilia can both mediate and suppress Hedgehog pathway–dependent tumorigenesis. Nat Med 15, 1055–1061 (2009). https://doi.org/10.1038/nm.2011

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