Abstract SY37-01: Cilia and wounding cooperate with Hedgehog signaling to initiate basal cell carcinoma

Abstract

Abstract Primary cilia are microtubule-based projections found on many human cells. These cilia do not move, but function as cellular antennae to receive and interpret signals. For example, olfactory cilia sense odorants in the environment. Other cilia sense cues from other cells, such as Hedgehog proteins, to coordinate tissue patterning and growth. We have identified mechanisms of ciliary signaling, cilium formation, and the regulation of ciliary composition. Defects in ciliary signaling cause some forms of birth defects, cancer, polycystic kidney disease, and other disorders collectively called ciliopathies. To examine whether cilia can participate in disorders beyond recognized ciliopathies, we assessed the prevalence of cilia in human tumors and the role of cilia in cancer. Human basal cell carcinomas (BCCs) are associated with misactivation of Hedgehog signaling, commonly through acquisition of mutations in Smoothened. We found that human BCCs are frequently ciliated. We tested the role of cilia in BCC by conditionally deleting genes required for ciliogenesis in a Hedgehog pathway-dependent mouse model of BCC. Ciliary ablation strongly inhibited BCC-like tumors induced by misactivation of the Hedgehog pathway at the level of Smoothened, revealing that BCC can be addicted to cilia. Skin tumors, like many other cancers, are associated with injury. Although stem cells participate in tissue regeneration after wounding, it is unclear whether these cells also contribute to epithelial tumors. Surprisingly, expression of an activated form of Smoothened by stem cells of the hair-follicle bulge and secondary hair germ does not induce robust Hedgehog signaling or produce BCCs. However, wounding recruits these cells from the follicle to the wound site, where downstream Hedgehog signal transduction is derepressed, giving rise to superficial BCC-like tumors. Thus, BCCs can originate from follicular stem cells and wounding can promote tumorigenesis by moving oncogene-expressing stem cells out of a suppressive niche. As we found that oncogenic Smoothened requires the cilium to promote tumorigenesis, we investigated how Smoothened moves to the cilium. We found that proteins of the Tectonic family form part of the transition zone, a region at the base of the cilium. Tectonic1 is an extracytosolic glycoprotein that interacts with transmembrane components of the transition zone to connect to a cytosolic transition zone complex comprised of the products of genes associated with two ciliopathies, Joubert and Meckel syndromes. Loss of components of the Tectonic transition zone complex in mice compromise ciliogenesis in some tissues, but in others, it is required for Smoothened and select other membrane proteins to localize to cilia. A complementary small molecule screen is identifying new chemicals that also prevent Smoothened localization to cilia and block oncogenic Hedgehog signaling. Interfering with the cellular machinery that moves Smoothened to cilia may be a complementary means of treating Hedgehog pathway-associated cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY37-01. doi:1538-7445.AM2012-SY37-01