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.Elevated Hh pathway activity is associated with diverse tumors, including basal cell carcinoma, the most commonly diagnosed cancer in North America 1,2 . Hh signaling is normally restrained by the tumor suppressor Patched (Ptch1), which inhibits the function of the protooncogene Smoothened (Smo), a central activator of the pathway 3 . Binding of Hh ligand to Ptch1 relieves its inhibition of Smo, allowing Smo to induce downstream Gli activators and inhibit the formation of Gli repressors. In BCCs, loss of function mutations in PTCH1, gain of function mutations in SMO, and upregulation of GLI1 and GLI2 are frequently observed, suggesting that dysregulated Hh signaling is the underlying cause of this disease [4][5][6][7][8] .Recent studies have shown that the primary cilium has a prominent role in modulating mammalian Hh signaling 9 . Ptch1 suppresses the Hh pathway, at least in part, by preventing the trafficking of Smo into the primary cilium 10 In addition to its essential role in transducing Hh signals, the cilium also negatively regulates the pathway. Genetic analyses have shown that the cilium is required for the proteolytic processing of Gli3 into a form that represses the Hh transcriptional program (Gli3-R) [12][13][14][15] . Cilium-dependent formation of Gli3-R occurs in the absence of Hh and is suppressed upon Smo movement to the cilium. Thus, the cilium exerts both positive and negative control over the Hh pathway.Although cilia are present on many vertebrate cells, their involvement in cancer has not been explored. Early ultrastructural studies have indicated that individual cells from human BCCs can be ciliated 16 ; however, the prevalence of these ciliated cells has remained unclear. To determine whether cancer cells frequently possess cilia, we examined clinical biopsies from eight human BCCs. We observed that five BCCs contained numerous ciliated cells ( Fig. 1a and Supplementary Fig. ...

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Current data indicate that localization of SMO to cilium is not sufficient to activate hedgehog signaling (Rohatgi et al, 2009;Wilson et al, 2009a). Using Kif3a tissue-specific gene knockout, recent studies revealed dual roles of cilium for hedgehog signaling carcinogenesis in mouse models Wong et al, 2009). Although Kif3a is required for SMO-mediated tumor formation, deletion of Kif3a accelerates Gli2-mediated carcinogenesis.…”

Primer and interviews: Diverse connections between primary cilia and Hedgehog signaling

“…More specifically, a subset of individuals with BCC harbor a mutant activated form of Smo that is constitutively localized to cilia. To investigate the role of cilia in oncogenesis, mouse models of BCC and medublastomas were generated by targeting constitutively active Smo to skin cells and cerebellar granule neuron precursors, respectively (Han et al, 2009;Wong et al, 2009). Strikingly, when Kif3a or Ift88 were genetically ablated in the altered cell types, tumor formation was inhibited.…”

Le fuseau mitotique, le centrosome et le cancer : trouvez l’intrus !

“…Cette découverte suggère que la ségrégation différentielle des centrioles en fonction de leur âge, et donc l'apparition asynchrone des cils, pourraient influencer le destin cellulaire des deux cellules filles et leur capacité à se différencier au sein d'un tissu. Un nombre important de mutations dans des gènes codant pour des molécules impliquées dans la ciliogenèse a été identifié dans des maladies génétiques, de nombreux syndromes (MeckelGruber), des maladies du rein (polykystose rénale) [42] et des cancers [43][44][45]. De plus, dans certains cas, l'identité des cellules souches dépend de leur positionnement.…”