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Neuroblastoma Cancer Stem Cells: the Role of NXPH1 and Its Receptor Α-NRXN1

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Neuroblastoma Cancer Stem Cells: the Role of NXPH1 and Its Receptor Α-NRXN1 Neuroblastoma cancer stem cells: The role of NXPH1 and its receptor α-NRXN1 Lucía Fanlo Escudero Aquesta tesi doctoral està subjecta a la llicència Reconeixement- NoComercial 4.0. Espanya de Creative Commons. Esta tesis doctoral está sujeta a la licencia Reconocimiento - NoComercial 4.0. España de Creative Commons. This doctoral thesis is licensed under the Creative Commons Attribution-NonCommercial 4.0. Spain License. UNIVERSITAT DE BARCELONA FACULTAD DE FARMÀCIA I CIÈNCIES DE L’ALIMENTACIÓ Neuroblastoma cancer stem cells: The role of NXPH1 and its receptor α-NRXN1 Lucía Fanlo Escudero 2019 UNIVERSITAT DE BARCELONA FACULTAT DE FARMÀCIA I CIÈNCIES DE L’ALIMENTACIÓ PROGRAMA DE DOCTORAT EN BIOMEDICINA Neuroblastoma cancer stem cells: The role of NXPH1 and its receptor α-NRXN1 Memoria presentada por Lucía Fanlo Escudero para optar al título de Doctora por la Universitat de Barcelona Este trabajo ha sido realizado bajo la dirección de la Dra. Elisa Martí Gorostiza y del Dr. Gwenvael Le Dréau, en el Instituto de Biología Molecular de Barcelona (IBMB-CSIC) Codirectores: Dra. Elisa Martí Gorostiza Dr. Gwenvael Le Dréau Doctoranda: Tutor: Lucía Fanlo Escudero Dr. Carles Enrich Bastús 2019 […] CLARA.- (Piensa:) ¿Cómo es posible que alguien quiera dormir cuando hay tanta hermosura en el aire, en las rocas, en los árboles? Yo no quiero dormir nunca, nunca; no quiero perder ni un segundo de vida, por que ahora que he visto la maravilla de esta noche, me figuro que siempre deben estar su- cediendo cosas maravillosas. Y si sucede una que no pueda ocurrir más que una vez y yo, por estarme durmiendo, no la veo, no me consolaré en mi vida entera. Una risita suave responde a los exaltados pensamientos de Clara. CLARA.- (Un poco avergonzada, pregunta:) ¿Quién se ríe de mí? […] Viajes de una gota de agua María de la O Lejárraga A mis padres, a mis hermanos, a Pablo SUMMARY SUMMARY Neuroblastoma (NB) is a devastating paediatric cancer that originates in the developing sympa- thetic nervous system. These tumours account for 40% of the cases of cancer diagnosed during the first year of life and 8% of the cases detected overall during childhood. They show a striking clinical di- versity, ranging from spontaneous remission to fatal metastatic dissemination. To optimize therapeu- tic approaches, NB patients have been stratified into risk groups. For the high risk (HR) patients, the 5 years overall survival probability remains below 30-40%. The failure to successfully treat these HR patients mainly results from the therapy-resistance and metastatic potential harboured by these tu- mours. The large intra-tumour heterogeneity of the HR tumours seems to be a key factor contributing to tumour progression. Thereby, there is an urgent need to understand the biological diversity of the HR-NBs in order to develop efficient therapies for these patients. Interestingly, NBs show a marked scarcity of recurrent genetic changes even during relapse, pointing towards a relevant role of non-ge- netic sources of tumour heterogeneity. Compelling evidences suggest the existence of cells possess- ing a tumour-propagating capacity, called cancer stem cells or tumour-propagating cells (CSCs/TPCs), in these HR-NB tumours. Defining the heterogeneity of NBs and their stemness potential is thus fun- damental to design new therapies targeting the driving force of the CSCs: their self-renewal ability. The general aim of this doctoral thesis was to identify a genetic signature for neuroblastoma can- cer stem cells (NBcsc), with the ultimate goal of providing new specific molecular markers of these NBcsc and candidate genes that might be useful for the development of future therapeutic strategies targeting the NBcsc in HR-NBs. It is assumed that NBcsc share many similarities with their normal stem cells counterparts, the neural crest cells (NCCs), which represent a transient embryonic popula- tion of pluripotent stem cells that give rise to the peripheral nervous system. Therefore, we compared the transcriptomic signature of NCCs with the transcriptomic profiles established for clinically rel- evant groups of NB patients. Among the candidates identified by our double screening, we retrieved Neurexophilin 1 (NXPH1): an extracellular glycoprotein known to bind to the transmembrane recep- tors of the alpha-Neurexin (α-NRXN) family. To determine whether NXPH1/α–NRXNs activity is effec- tively related to NBcsc, we analysed their expression in a panel of human NB cell lines in conditions of stem cell enrichment. The marked induction of α-NRXN1/2 mRNA levels in the stem cell-enriched fraction suggested that they might be NBcsc markers. We identified the existence of a low subpopu- lation of α-NRXN1+ cells in samples from human NB cell lines and patient-derived xenografts. We further established that these α-NRXN1+ cells represent a functionally discrete subpopulation of NB cells characterized by: 1) an active cycling behaviour, 2) an increased self-renewal capacity, and 3) a higher probability to survive upon chemotherapeutic insult. Our data suggest that these α-NRXN1+ NB cells are endowed with a tumour-propagating capacity and that they are required to sustain tu- SUMMARY mour growth in vivo. In parallel, we investigated whether NXPH1 is implicated in NB malignancy. Our data revealed that NXPH1 promotes NB growth, possibly by stimulating the proliferation of actively dividing NB cells and by increasing the proportion of NB cells expressing the NCC stem cell marker p75NTR. Finally, we showed that inhibiting NXPH1 or α-NRXN1 activity abrogates NB tumour growth in xenograft models. Our work provides the first experimental evidence that NXPH1, probably acting through its re- ceptor α-NRXN1, exerts a functional role in NB progression. We suggest that NXPH1, present in the tumour microenvironment, controls the tumour-propagating capacity of NBcsc and that its reduced activity might facilitate the malignant progression of these tumours by enabling NBcsc to acquire a metastatic capacity. RESUMEN RESUMEN El neuroblastoma (NB) es un tumor pediátrico del sistema nervioso simpático en desarrollo. La probabilidad de supervivencia de los pacientes de alto riesgo no supera el 30-40%. El estudio de la heterogeneidad celular del NB revela la probable existencia de células con capacidad de propagación tumoral (en inglés cancer stem cells, CSCs). Su identificación y caracterización es fundamental en la búsqueda de nuevos fármacos para dichos pacientes. El objeto de esta tesis doctoral ha sido la identificación de la huella genética de las CSCs en el NB con la finalidad de identificar marcadores moleculares específicos y nuevas dianas terapéuticas. Para ello, partimos de la premisa de que lasCSCs de los NBs deben de compartir ciertas características con sus equivalentes en el tejido sano, las células de la cresta neural (en inglés neural crest cells, NCCs), una población embrionaria de células madre que origina el sistema nervioso periférico. Al comparar el transcriptoma de las NCCs con el extraído de una comparación entre grupos de pacientes con rel- evancia clínica, seleccionamos la Neurexofilina 1 (NXPH1), un ligando extracelular de las Neurexinas alfa (α-NRXN). Para determinar si ambos están relacionados con el fenotipo de CSCs, analizamos su expresión en una colección de líneas celulares en condiciones de enriquecimiento para dicho feno- tipo. El marcado aumento en los niveles de RNA mensajero de α-NRXN1/2 sugirió que podrían fun- cionar como marcadores de las CSCs. Hemos confirmado la existencia de una población α-NRXN1+ caracterizada por una mayor capacidad de proliferación, de replicación y de pervivencia a quimiotera- pia. Las células α-NRXN1+ presentan características de CSCs y son requeridas para el crecimiento tu- moral. En paralelo vemos que NXPH1 promueve el crecimiento tumoral estimulando la proliferación y la presencia de células p75NTR+, marcador asociado a las NCCs. Además, la inhibición de NXPH1 o α-NRXN1 impide el crecimiento tumoral en modelos experimentales. Este trabajo constituye la primera evidencia funcional del papel de NXPH1 en la progresión del NB. Sugerimos que NXPH1, probablemente a través de α-NRXN1, participa en la regulación de la capaci- dad de propagación tumoral y que su pérdida favorece la adquisición de rasgos asociados a pacientes de alto riesgo. TABLE OF CONTENTS TABLE OF CONTENTS ABBREVIATIONS V LIST OF FIGURES VII LIST OF TABLES IX I. INTRODUCTION.............................................................................................................................1 1. The neural crest............................................................................................................................3 1.1. Induction, specification, delamination and migration........................................................ 3 1.2. NCCs derivatives...................................................................................................................5 1.3. Differentiation of the sympathoadrenal lineages................................................................6 1.4. NCC-associated pathologies.................................................................................................8 2. Neuroblastoma: a paediatric tumour deriving from the embryonic sympathoadrenal lineage..8 2.1. Prevalence............................................................................................................................8 2.2. Origin....................................................................................................................................9
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