The role of primary cilia in cancer

Primary cilia are microtubule based organelles that sense and transduce multiple extracellular signals to the interior of the cell through several signaling pathways. Ciliary defects lead to different pathologies. Interestingly, decreased ciliary expression has been associated with different types of cancer. In this review, we discuss the function and dynamics of primary cilia, their relation to different diseases and in particular their role in cancer, and how they can be explored as potential therapeutic targets.Sociedad Argentina de Fisiologí

Synthetic conjugates of ursodeoxycholic acid inhibit cystogenesis in experimental models of polycystic liver disease

Background and aims: polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and results: here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: these UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs

Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease

Background and Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.Supported by the Spanish Carlos III Health Institute (ISCIII; J.M. Banales: FIS PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129; M.J. Perugorria: PI14/00399, PI17/00022; J.J.G. Marin: FIS PI16/00598) cofinanced by "Fondo Europeo de Desarrollo Regional" (FEDER); CIBERehd (ISCIII): J.M. Banales, M.J. Perugorria, L. Bujanda, and J.J.G. Marin; Spanish Ministry of Economy and Competitiveness (M. J. Perugorria: Ramon y Cajal Program RYC-2015-17755); IKERBASQUE, Basque foundation for Science (M.J. Perugorria and J.M. Banales), Spain; "Junta de Castilla y Leon" (J.J.G. Marin: SA06P17); " Diputacion Foral Gipuzkoa" (J.M. Banales: DFG15/010, DFG16/004; M.J. Perugorria: DFG18/114, DFG19/081), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales), Department of Health of the Basque Country (J.M. Banales: 2017111010; M.J. Perugorria: 2019111024), and Euskadi RIS3 (J.M. Banales: 2016222001, 2017222014, and 2018222029; 2019222054); La Caixa Scientific Foundation (J.M. Banales: HR17-00601); "Fundacion Cientifica de la Asociacion Espanola Contra el Cancer" (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); and "Centro Internacional sobre el Envejecimiento", Spain (J.J.G. Marin: OLD-HEPAMARKER, 0348-CIE-6-E). F.J. Caballero-Camino was funded by the Spanish Ministry of Science and Innovation (BES-2014-069148), A. Santos-Laso by the Basque Government (PRE_2018_2_0195), and Pui Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award). The Spanish Ministry of Science and Innovation supported F. P. Cossio: (CTQ2016-80375-P and CTQ2014-51912-REDC) as well as the Basque Government (F.P. Cossio: IT-324-07). I. Rivilla had a postdoctoral contract from the Donostia International Physics Center

Cholangiocarcinoma 2020: the next horizon in mechanisms and management

[EN] Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non- invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlightedJ.M.B. received EASL Registry Awards 2016 and 2019 (European CCA Registry, ENS-CCA). J.M.B. and M.J.P. were supported by: the Spanish Ministry of Economy and Competitiveness (J.M.B.: FIS PI12/00380, FIS PI15/01132, FIS PI18/01075 and Miguel Servet Programme CON14/00129; M.J.P.: FIS PI14/00399, FIS PI17/00022 and Ramon y Cajal Programme RYC-2015-17755, co-financed by “Fondo Europeo de Desarrollo Regional” (FEDER)); ISCIII CIBERehd; “Diputación Foral de Gipuzkoa” (J.M.B: DFG15/010, DFG16/004), and BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD); the Department of Health of the Basque Country (M.J.P.: 2015111100; J.M.B.: 2017111010), and “Fundación Científica de la Asociación Española Contra el Cancer” (AECC Scientific Foundation) (J.M.B.). J.M.B. and J.W.V. were supported by the European Commission Horizon 2020 programme (ESCALON project 825510). The laboratory of J.B.A. is supported by competitive grants from the Danish Medical Research Council, the Danish Cancer Society, and the Novo Nordisk and A.P. Møller Foundations. J.J.G.M. and R.I.R.M. were supported by the Carlos III Institute of Health, Spain (PI16/00598 and PI18/00428) and were co-financed by the European Regional Development Fund. J.M.B. and J.J.G.M. were supported by the Ministry of Science and Innovation, Spain (SAF2016-75197-R), and the “Asociación Española Contra el Cancer”, Spain (AECC-2017). R.I.R.M. was supported by the “Centro Internacional sobre el Envejecimiento”, Spain (OLD-HEPAMARKER, 0348-CIE-6-E). A.L. received funding from the Christie Charity. M.M. was supported by the Università Politecnica delle Marche, Ancona, Italy (040020_R.SCIENT.A_2018_MARZIONI_M_STRATEGICO_2017). M.S. was supported by the Yale Liver Center Clinical and Translational Core and the Cellular and Molecular Core (DK034989 Silvio O. Conte Digestive Diseases Research Center). C.C. is supported by grants from INSERM, Université de Rennes, INCa, and ITMO Cancer AVIESAN dans le cadre du Plan Cancer (Non-coding RNA in Cancerology: Fundamental to Translational), Ligue Contre le Cancer and Région Bretagne. J.Bruix was supported by grants from Instituto de Salud Carlos III (PI18/00763), AECC (PI044031) and WCR (AICR) 16-0026. A.F. was supported by grants from ISCIII (PI13/01229 and PI18/00542). CIBERehd is funded by the Instituto de Salud Carlos III. V.C., D.M., J. Bridgewater and P.I. are members of the European Reference Network - Hepatological Diseases (ERN RARE-LIVER). J.M.B. is a collaborator of the ERN RARE-LIVER

Cilia and Cancer: From Molecular Genetics to Therapeutic Strategies

: Cilia are microtubule-based organelles that project from the cell surface with motility or sensory functions. Primary cilia work as antennae to sense and transduce extracellular signals. Cilia critically control proliferation by mediating cell-extrinsic signals and by regulating cell cycle entry. Recent studies have shown that primary cilia and their associated proteins also function in autophagy and genome stability, which are important players in oncogenesis. Abnormal functions of primary cilia may contribute to oncogenesis. Indeed, defective cilia can either promote or suppress cancers, depending on the cancer-initiating mutation, and the presence or absence of primary cilia is associated with specific cancer types. Together, these findings suggest that primary cilia play important, but distinct roles in different cancer types, opening up a completely new avenue of research to understand the biology and treatment of cancers. In this review, we discuss the roles of primary cilia in promoting or inhibiting oncogenesis based on the known or predicted functions of cilia and cilia-associated proteins in several key processes and related clinical implications

Primers on molecular pathways - ion channels: key regulators of pancreatic physiology

Ion transport across the cellular plasma membrane is important in almost every physiological process. This phenomenon is driven by the coordinated action of carriers, pumps and channels, which move ions in and out the cells and between different organelles. Ion channels are transmembrane proteins that provide a continuous aqueous pore through which ions can selectively move. The interest in these molecules has increased due to the recognition of diverse pathologies related with mutations in genes encoding these transmembrane proteins, now known as channelopathies. Ion channels play a variety of functions in the pancreas. Here, we briefly describe ion transport characteristics as well as their role in pancreas physiology and pathophysiology

Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a highly invasive and metastatic form of carcinoma with bleak prognosis due to limited therapies, frequent relapse, and chemotherapy resistance. There is an urgent need to identify the molecular regulators of CCA in order to develop novel therapeutics and advance diseases diagnosis. Many cellular proteins including histones may undergo a series of enzyme-mediated post-translational modifications including acetylation, methylation, phosphorylation, sumoylation, and crotonylation. Histone deacetylases (HDACs) play an important role in regulating epigenetic maintenance and modifications of their targets, which in turn exert critical impacts on chromatin structure, gene expression, and stability of proteins. As such, HDACs constitute a group of potential therapeutic targets for CCA. The aim of this review was to summarize the role that HDACs perform in regulating epigenetic changes, tumor development, and their potential as therapeutic targets for CCA