Squamous cell carcinoma (SCC) of the head and neck originates from the mucosal lining of the upper aerodigestive tract, including the lip, tongue, nasopharynx, oropharynx, larynx and hypopharynx. In this review, we summarise what is currently known about the potential function of primary cilia in the pathogenesis of this disease. As primary cilia represent a key cellular structure for signal transduction and are related to cell proliferation, an understanding of their role in carcinogenesis is necessary for the design of new treatment approaches. Here, we introduce cilia-related signalling in head and neck squamous cell carcinoma (HNSCC) and its possible association with HNSCC tumorigenesis. From this point of view, PDGF, EGF, Wnt and Hh signalling are discussed as all these pathways were found to be dysregulated in HNSCC. Moreover, we review the clinical potential of small molecules affecting primary cilia signalling to target squamous cell carcinoma of the head and neck area.

The hexanucleotide G4C2 repeat expansion (HRE) in C9ORF72 gene is the major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to both loss- and gain-of-function pathomechanisms. The wide clinical heterogeneity among C9ORF72 patients suggests potential modifying genetic and epigenetic factors. Notably, C9ORF72 HRE often co-occurs with other rare variants in ALS/FTD-associated genes, such as NEK1, which encodes for a kinase involved in multiple cell pathways, including DNA damage response and ciliogenesis. In this study, we generated induced pluripotent stem cells (iPSCs) and differentiated motoneurons (iPSC-MNs) from an ALS patient carrying both C9ORF72 HRE and a NEK1 loss-of-function mutation to investigate the biological effect of NEK1 haploinsufficiency on C9ORF72 pathology in a condition of oligogenicity. Double mutant C9ORF72/NEK1 cells showed increased pathological C9ORF72 RNA foci in iPSCs and higher DNA damage levels in iPSC-MNs compared to single mutant C9ORF72 cells, but no effect on DNA damage response. When we analysed the primary cilium, we observed a defective ciliogenesis in C9ORF72 iPSC-MNs which was not worsened by NEK1 haploinsufficiency in the double mutant iPSC-MNs. Altogether, our study shows that NEK1 haploinsufficiency influences differently DNA damage and cilia length, potentially acting as a modifier at biological level in an in vitro ALS patient-derived disease model of C9ORF72 pathology.

An association between high CD47 expression and poor cancer survival has been attributed to its function on malignant cells to inhibit phagocytic clearance. However, CD47 mRNA expression in some cancers lacks correlation or correlates with improved survival. IFT57 encodes an essential primary cilium component and is colinear with CD47 across amniote genomes, suggesting coregulation of these genes. Analysis of The Cancer Genome Atlas datasets identified IFT57 as a top coexpressed gene with CD47 among 1156 human cancer cell lines and in most tumor types. The primary cilium also regulates cancer pathogenesis, and correlations between IFT57 mRNA and survival paralleled those for CD47 in thyroid and lung carcinomas, melanoma, and glioma. CD47 ranked first for coexpression with IFT57 mRNA in papillary thyroid carcinomas, and higher expression of both genes correlated with significantly improved overall survival. CD47 and IFT57 mRNAs were coordinately regulated in thyroid carcinoma cell lines. Transcriptome analysis following knockdown of CD47 or IFT57 in thyroid carcinoma cells identified the cytoskeletal regulator CRACD as a specific target of IFT57. CRACD mRNA expression inversely correlated with IFT57 mRNA and with survival in low-grade gliomas, lung adenocarcinomas, and papillary thyroid carcinomas, suggesting that IFT57 rather than CD47 regulates survival in these cancers.

Philadelphia-Negative Myeloproliferative neoplasms (MPNs) are a diverse group of blood cancers leading to excessive production of mature blood cells. These chronic diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), can significantly impact patient quality of life and are still incurable in the vast majority of the cases. This review examines the mechanobiology within a bone marrow niche, emphasizing the role of mechanical cues and the primary cilium in the pathophysiology of MPNs. It discusses the influence of extracellular matrix components, cell-cell and cell-matrix interactions, and mechanosensitive structures on hematopoietic stem cell (HSC) behavior and disease progression. Additionally, the potential implications of the primary cilium as a chemo- and mechanosensory organelle in bone marrow cells are explored, highlighting its involvement in signaling pathways crucial for hematopoietic regulation. This review proposes future research directions to better understand the dysregulated bone marrow niche in MPNs and to identify novel therapeutic targets.

Ciliopathies are characterized by the absence or dysfunction of primary cilia. Despite the fact that cognitive impairments are a common feature of ciliopathies, how cilia dysfunction affects neuronal development has not been characterized in detail. Here, we show that primary cilium-mediated signaling is required cell-autonomously by neurons during neural circuit formation. In particular, a functional primary cilium is crucial during axonal pathfinding for the switch in responsiveness of axons at a choice point or intermediate target. Using different animal models and in vivo, ex vivo and in vitro experiments, we provide evidence for a crucial role of primary cilium-mediated signaling in long-range axon guidance. The primary cilium on the cell body of commissural neurons transduces long-range guidance signals sensed by growth cones navigating an intermediate target. In extension of our finding that Shh is required for the rostral turn of post-crossing commissural axons, we suggest a model implicating the primary cilium in Shh signaling upstream of a transcriptional change of axon guidance receptors, which in turn mediate the repulsive response to floorplate-derived Shh shown by post-crossing commissural axons.

OBJECTIVE: Pediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly.
METHODS: In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test.
RESULTS: A likely causal variant was identified in 135 families (48.56%). These comprise 135 families that harbor variants spanning 37 genes with established or tentative links to cholestasis. In addition, we propose a novel candidate gene (PSKH1) (HGNC:9529) in 4 families. PSKH1 was particularly compelling because of strong linkage in three consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the four families shared a founder homozygous variant while the third had a different homozygous variant in PSKH1. PSKH1 encodes a putative protein serine kinase of unknown function. Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays.
CONCLUSIONS: Our results support the use of genomics in the workup of pediatric cholestasis and reveal PSKH1-related hepatorenal ciliopathy as a novel candidate monogenic form.

The cilium, a pivotal organelle crucial for cell signaling and proper cell function, relies on meticulous macromolecular transport from the cytoplasm for its formation and maintenance. While the intraflagellar transport (IFT) pathway has traditionally been the focus of extensive study concerning ciliogenesis and ciliary maintenance, recent research highlights a complementary and alternative mechanism-vesicle-assisted transport (VAT) in cytoplasm to cilium trafficking. Despite its potential significance, the VAT pathway remains largely uncharacterized. This review explores recent studies providing evidence for the dynamics of vesicle-related diffusion and transport within the live primary cilium, employing high-speed super-resolution light microscopy. Additionally, we analyze the spatial distribution of vesicles in the cilium, mainly relying on electron microscopy data. By scrutinizing the VAT pathways that facilitate cargo transport into the cilium, with a specific emphasis on recent advancements and imaging data, our objective is to synthesize a comprehensive model of ciliary transport through the integration of IFT-VAT mechanisms.

Centriolar satellites are ubiquitous membrane-less organelles that play critical roles in numerous cellular and organismal processes. They were initially discovered through electron microscopy as cytoplasmic granules surrounding centrosomes in vertebrate cells. These structures remained enigmatic until the identification of pericentriolar material 1 protein (PCM1) as their molecular marker, which has enabled their in-depth characterization. Recently, centriolar satellites have come into the spotlight due to their links to developmental and neurodegenerative disorders. This review presents a comprehensive summary of the major advances in centriolar satellite biology, with a focus on studies that investigated their biology associated with the essential scaffolding protein PCM1. We begin by exploring the molecular, cellular, and biochemical properties of centriolar satellites, laying the groundwork for a deeper understanding of their functions and mechanisms at both cellular and organismal levels. We then examine the implications of their dysregulation in various diseases, particularly highlighting their emerging roles in neurodegenerative and developmental disorders, as revealed by organismal models of PCM1. We conclude by discussing the current state of knowledge and posing questions about the adaptable nature of these organelles, thereby setting the stage for future research.

C3-positive reactive astrocytes play a neurotoxic role in various neurodegenerative diseases. However, the mechanisms controlling C3-positive reactive astrocyte induction are largely unknown. We found that the length of the primary cilium, a cellular organelle that receives extracellular signals was increased in C3-positive reactive astrocytes, and the loss or shortening of primary cilium decreased the count of C3-positive reactive astrocytes. Pharmacological experiments suggested that Ca2+ signalling may synergistically promote C3 expression in reactive astrocytes. Conditional knockout (cKO) mice that specifically inhibit primary cilium formation in astrocytes upon drug stimulation exhibited a reduction in the proportions of C3-positive reactive astrocytes and apoptotic cells in the brain even after the injection of lipopolysaccharide (LPS). Additionally, the novel object recognition (NOR) score observed in the cKO mice was higher than that observed in the neuroinflammation model mice. These results suggest that the primary cilium in astrocytes positively regulates C3 expression. We propose that regulating astrocyte-specific primary cilium signalling may be a novel strategy for the suppression of neuroinflammation.

The primary cilium, hereafter cilium, is an antenna-like organelle that modulates intracellular responses, including autophagy, a lysosomal degradation process essential for cell homeostasis. Dysfunction of the cilium is associated with impairment of autophagy and diseases known as \"ciliopathies\". The discovery of autophagy-related proteins at the base of the cilium suggests its potential role in coordinating autophagy initiation in response to physiopathological stimuli. One of these proteins, beclin-1 (BECN1), it which is necessary for autophagosome biogenesis. Additionally, polycystin-2 (PKD2), a calcium channel enriched at the cilium, is required and sufficient to induce autophagy in renal and cancer cells. We previously demonstrated that PKD2 and BECN1 form a protein complex at the endoplasmic reticulum in non-ciliated cells, where it initiates autophagy, but whether this protein complex is present at the cilium remains unknown. Anorexigenic pro-opiomelanocortin (POMC) neurons are ciliated cells that require autophagy to maintain intracellular homeostasis. POMC neurons are sensitive to metabolic changes, modulating signaling pathways crucial for controlling food intake. Exposure to the saturated fatty acid palmitic acid (PA) reduces ciliogenesis and inhibits autophagy in these cells. Here, we show that PKD2 and BECN1 form a protein complex in N43/5 cells, an in vitro model of POMC neurons, and that both PKD2 and BECN1 locate at the cilium. In addition, our data show that the cilium is required for PKD2-BECN1 protein complex formation and that PA disrupts the PKD2-BECN1 complex, suppressing autophagy. Our findings provide new insights into the mechanisms by which the cilium controls autophagy in hypothalamic neuronal cells.