Primary cilia and cancer: a tale of many faces

Abstract

Cilia are microtubule-based sensory organelles which project from the cell surface, enabling detection of mechanical and chemical stimuli from the extracellular environment. It has been shown that cilia are lost in some cancers, while others depend on cilia or ciliary signaling. Several oncogenic molecules, including tyrosine kinases, G-protein coupled receptors, cytosolic kinases, and their downstream effectors localize to cilia. The Hedgehog pathway, one of the most studied ciliary-signaling pathways, is regulated at the cilium via an interplay between Smoothened (an oncogene) and Patched (a tumor suppressor), resulting in the activation of pro-survival programs. Interestingly, cilia loss can result in resistance to Smoothened-targeting drugs and increased cancer cell survival. On the other hand, kinase inhibitor-resistant and chemoresistant cancers have increased cilia and increased Hedgehog pathway activation, and suppressing cilia can overcome this resistance. How cilia regulate cancer is therefore context dependent. Defining the signaling output of cilia-localized oncogenic pathways could identify specific targets for cancer therapy, including the cilium itself. Increasing evidence implicates cilia in supporting several hallmarks of cancer, including migration, invasion, and metabolic rewiring. While cell cycle cues regulate the biogenesis of cilia, the absence of cilia has not been conclusively shown to affect the cell cycle. Thus, a complex interplay between molecular signals, phosphorylation events and spatial regulation renders this fascinating organelle an important new player in cancer through roles that we are only starting to uncover. In this review, we discuss recent advances in our understanding of cilia as signaling platforms in cancer and the influence this plays in tumor development.

Fig. 1. Cilium cycle and structure.

A In G1 (and G0), the mother centriole [1] and daughter centriole [2] are linked. The mother centriole is modified with distal and subdistal appendages and functions as a basal body, which docks to the plasma membrane. The ciliary axoneme extends from the basal body, protruding from the cell surface. The cilium persists into G2/M-phase but is disassembled prior to cytokinesis. Centrioles duplicate in S-phase, with centrioles [3, 4] growing off the original mother [1] and daughter [2] centrioles. These new centrioles mature during G2-phase. The tether (cohesion fibers) connecting the mother [1] and daughter [2] centrioles breaks at the beginning of M-phase, with the two centriole pairs [1 and 3, 2 and 4] later acting as MTOCs during chromosome separation. Each daughter cell receives a new mother/daughter centriole pair, and the cycle begins again. B The primary cilium consists of a microtubule-based axoneme extending from the basal body, a mother centriole modified by distal and subdistal appendages. The cilium is enriched in signaling receptors and effectors. Transport of molecules in and out of the cilium is regulated by the transition zone and mediated by IFT machinery. Created with BioRender.com.

Fig. 2. Dysfunction of ciliary proteins leads to a wide range of ciliopathies.

Mutations in genes encoding proteins required for ciliary assembly and/or function lead to the development of ciliopathies, such as the above examples of autosomal dominant polycystic kidney disease, orofacialdigital syndrome 1, and Alström syndrome. Despite affecting the same organelle, these mutations affect a variety of organ systems and cause distinct disease phenotypes. Abbreviations: PC1 polycystin 1, PC2 polycystin 2, PKD1 polycystic kidney disease 1, OFD1 orofacialdigital syndrome 1 protein, ALMS1 Alström syndrome 1. PKD1 is the gene encoding PC1. Created with BioRender.com.

Fig. 3. Hedgehog signaling at the cilium in tumorigenesis.

A In the off state, SMO entry to the cilium is restricted by PTCH1. SUFU sequesters GLI transcription factors at the tip of the cilium. GLI factors are also phosphorylated by a complex of GSK3β, PKA, and CK1, promoting their partial processing to GLI repressors. B Upon Hh ligand binding to PTCH1, SMO may enter the ciliary membrane and suppress SUFU, relieving the suppression of GLI. Full-length activatory GLI can enter the nucleus and drive target gene transcription. C Models of medulloblastoma and BCC with constitutive ciliary SMO localization show increased cell proliferation and tumor development, which was inhibited by ciliary ablation via KIF3A deletion. D Models of medulloblastoma and BCC with constitutively active GLI2 display increased cell proliferation. Tumor development was observed earlier upon cilia ablation via KIF3A deletion, but also occurred in the presence of cilia [19, 20]. Abbreviations: CK1 casein kinase 1, GLI-A activatory GLI, GLI-R repressor GLI, GSK3β = glycogen synthase kinase 3β. Created with BioRender.com.

Fig. 4. Cilia and ciliary signaling contribute to therapeutic resistance.

Ciliary Hh signaling promotes the transcription of genes associated with therapeutic resistance, including those promoting survival, stem cell behavior, and drug efflux. Ciliogenesis-promoting pathways, such as activation of the DNA damage response upon chemotherapeutic treatment, enhance ciliary signaling and consequently drive resistance. Created with BioRender.com.

Fig. 5. The many faces of cilia in cancer.

Primary cilia have been implicated in many of the hallmarks of cancer [33]. Tumors can display different dependencies on cilia and ciliary signaling, requiring investigation into individual patients and subtypes. Cilia could represent a novel target to restrict cancer progression in those tumors which are dependent on ciliary signaling. Created with BioRender.com.