4.6 Review

Cilia and Cancer: From Molecular Genetics to Therapeutic Strategies

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Review Cell Biology

Crosstalk between cilia and autophagy: implication for human diseases

Manuela Morleo et al.

Summary: Macroautophagy/autophagy is a self-degradative process that helps cells maintain energy balance. It has been found to have an interplay with cilia, microtubule-based organelles on mammalian cells. The selective autophagic degradation of ciliary proteins controls ciliogenesis, and cilia also control autophagy. The molecular mechanisms underlying this interaction are still not fully understood, and conflicting data exist. Understanding this axis is important for ciliopathies and autophagy-associated disorders.

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Summary: Activating BRAF mutations are present in 50-60% of malignant melanomas. Inhibiting EZH2 or its downstream target PLK1, in combination with BRAF inhibitors, may provide potential novel therapeutic options for melanomas with BRAF mutations.

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Loss of Primary Cilia Potentiates BRAF/MAPK Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (CROCC) Alterations

Andrea Remo et al.

Summary: A recent study explores the genetic and immunophenotypic characteristics of rhabdoid colorectal tumors (RCTs). The findings reveal that RCTs exhibit mismatch repair-deficient phenotypes, CK7-/CK20-/CDX2- marker phenotype, and aberrant activation of the MAPK pathway, particularly with BRAF V600E mutations. While SMARCB1/INI1 expression is normal, the ciliogenic markers CROCC and β-tubulin are globally altered in RCTs. Overall, these results indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs, suggesting a potential therapeutic target.
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Abnormal accumulation of OFD1 in endometrial cancer with poor prognosis inhibits ciliogenesis

Ryuji Kojima et al.

Summary: The aim of the study was to investigate primary cilia in endometrial tissue during the menstrual cycle and their morphological changes in different grades of endometrial cancer. The study found that there were fewer ciliated cells and shorter primary cilia in highly malignant endometrial cancer tissues. The expression of OFD1 was significantly higher in high-grade endometrial cancer.

ONCOLOGY LETTERS (2022)

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Predictive molecular patholoav in metastatic thyroid cancer: the role of RET fusions

Mariantonia Nacchio et al.

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Structural Biology of Cilia and Intraflagellar Transport

Nikolai Klena et al.

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Primary cilia control translation and the cell cycle in medulloblastoma

Yong Ha Youn et al.

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Targeting the MITF/APAF-1 axis as salvage therapy for MAPK inhibitors in resistant melanoma

Pietro Carotenuto et al.

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Modulation of Primary Cilia by Alvocidib Inhibition of CILK1

Elena X. Wang et al.

Summary: In this study, we identified a small molecular inhibitor called Alvocidib that can potently inhibit CILK1, promote cilia elongation, and selectively inhibit other protein kinases.

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Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis

Rebecca V. Walker et al.

Summary: TULP3 is a key adapter involved in cystogenesis, inhibiting cyst formation during kidney development but promoting it in adults. This review discusses the mechanism of cilia-dependent cyst activation in autosomal dominant polycystic kidney disease (ADPKD) and proposes the existence of cilia-localized components that determine cystogenesis.

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Loss of primary cilia promotes inflammation and carcinogenesis

Conception Paul et al.

Summary: This study found that a decrease in primary cilia numbers in the colon promotes colitis and colorectal cancer, and an activation loop may exist between the inflammatory environment and IL-6 production in relation to primary cilia loss.

EMBO REPORTS (2022)

Review Genetics & Heredity

EV duty vehicles: Features and functions of ciliary extracellular vesicles

Ludovic Vinay et al.

Summary: The primary cilium is an important sensor of the cell micro-environment and can emit signals through the release of extracellular vesicles (EVs), which participate in intercellular communication. These ciliary EVs carry unique markers and molecules and play an important role in organ development and homeostatic control.

FRONTIERS IN GENETICS (2022)

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Notch signaling pathway: architecture, disease, and therapeutics

Binghan Zhou et al.

Summary: The NOTCH gene and signaling pathway have been studied for 110 years and play important roles in the development, homeostasis, and related diseases of tissues and organs. However, recent studies have found that the outcomes of NOTCH signaling are context-dependent. In terms of cancer, NOTCH signaling can both promote and inhibit tumor development. NOTCH-targeted therapies in clinical trials have not met expectations, and NOTCH mutations may serve as predictive biomarkers for immune checkpoint blockade therapy in many cancers.

SIGNAL TRANSDUCTION AND TARGETED THERAPY (2022)

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Cilia and polycystic kidney disease

Ming Ma

Summary: Polycystic kidney disease (PKD) encompasses both autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), with mutations in different genes leading to the two forms. The pathogenesis and molecular mechanisms of PKD involve complex interplays between various proteins and signaling pathways, with potential implications for future therapeutic interventions.

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Genotoxic stress-activated DNA-PK-p53 cascade and autophagy cooperatively induce ciliogenesis to maintain the DNA damage response

Ting-Yu Chen et al.

Summary: The DNA-PK-p53 cascade induces primary cilia formation under genotoxic stress, contributing to the DNA damage response, while lack of this pathway decreases genotoxic stress-induced ciliogenesis. Besides, ciliogenesis is regulated not only by DNA-PK, but also by autophagy.

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Regulation of autophagosome biogenesis by OFD1-mediated selective autophagy

Manuela Morleo et al.

Summary: A negative feedback mechanism limiting autophagosome biogenesis by degrading ATG13 is discovered, with OFD1 acting as an autophagy receptor for ATG13. Mutations in the OFD1 gene may lead to excessive autophagy, implicating dysregulated autophagy in the pathogenesis of renal cystic disease in mammals.

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Whole-genome screen identifies diverse pathways that negatively regulate ciliogenesis

Marion Failler et al.

Summary: A novel gene network linking integrin signaling and cellular adhesion to the extracellular matrix (ECM) with inhibition of ciliation in both normal and cancer cells was identified. The potential mechanistic basis may involve the regulation of the YAP/TAZ pathway. These findings reveal an unexpected reciprocal relationship between ciliogenesis and cellular adhesion to the ECM.

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The Role of CDK5 in Tumours and Tumour Microenvironments

Phuong Anh Do et al.

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Motility of efferent duct cilia aids passage of sperm cells through the male reproductive system

Isabella Aprea et al.

Summary: Recent studies have shown that the motility of efferent duct cilia is crucial for male reproductive fitness in both mice and humans. Deficiency of the DNAH5 gene can lead to obstructive oligozoospermia, affecting male fertility but not sperm motility. Further research on environmental factors or genes causing efferent duct cilia dysmotility may provide insights into other causes of oligozoospermia.

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Loss of primary cilia promotes mitochondria-dependent apoptosis in thyroid cancer

Junguee Lee et al.

Summary: The primary cilium is well-preserved in human differentiated thyroid cancers, but specific types of thyroid cancers associated with abnormalities in mitochondrial function show reduced biogenesis of primary cilia. Experimental results suggest that defective ciliogenesis caused by loss-of-function of primary cilia in thyroid cancer cells can lead to apoptogenic stimuli and mitochondrial-dependent apoptotic cell death.

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Lan-ya Li et al.

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IFT20 Mediates the Transport of Cell Migration Regulators From the Trans-Golgi Network to the Plasma Membrane in Breast Cancer Cells

Huihui Yang et al.

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The Evolving Role of FGFR2 Inhibitors in Intrahepatic Cholangiocarcinoma: From Molecular Biology to Clinical Targeting

Massimiliano Salati et al.

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Cilium Expression Score Predicts Glioma Survival

Srinivas Rajagopalan et al.

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FRONTIERS IN GENETICS (2021)

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Ciliary extracellular vesicles are distinct from the cytosolic extracellular vesicles

Ashraf M. Mohieldin et al.

Summary: Extracellular vesicles (EVs) are cell-derived membrane vesicles that mediate intercellular signalling pathways. Primary cilia, mechanosensory organelles, are associated with human diseases. This study found distinct protein profiles between ciliary EVs and cytosolic EVs, highlighting unique differences in vesicles secreted from cilia and the cytosol.

JOURNAL OF EXTRACELLULAR VESICLES (2021)

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Intraflagellar Transport Proteins as Regulators of Primary Cilia Length

Wei Wang et al.

Summary: This article discusses the functions of primary cilia as important organelles and their significance in ciliary-related diseases; it also explores the mechanisms and factors involved in maintaining optimal cilia length, as well as the roles of IFT in cilia assembly/disassembly processes.

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Histone Deacetylase Sirtuin 1 Promotes Loss of Primary Cilia in Cholangiocarcinoma

Kishor Pant et al.

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Kousuke Kasahara et al.

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Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

Alexandru Nita et al.

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Diverse plasma membrane protrusions act as platforms for extracellular vesicle shedding

Kirsi Rilla

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