Neuroblastoma cancer stem cells: the role of nxph1 and its receptor α-nrxn1
- Autores: Lucía Fanlo
- Directores de la Tesis: Elisa Martí Gorostiza (dir. tes.), Le Dréau Gwenvael (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Miguel Francisco Segura Ginard (presid.), Eva González Suárez (secret.), Álvaro Rada Iglesias (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
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- Resumen
SUMMARY Neuroblastoma (NB) is a devastating paediatric cancer that originates in the developing sympathetic nervous system. They account for 40% of the cases of cancer diagnosed during the first year of life and 8% of the cases diagnosed overall during childhood. These tumours show a striking clinical diversity, ranging from spontaneous remission to fatal metastatic dissemination. To optimize therapeutic approaches,NB patients have been stratified into risk groups. For the high risk (HR) patients, the 5 years overall survivalprobability remains below 30-40%. The failure to successfully treat these HR patients mainly results from the therapy-resistance and metastatic potential harboured by these tumours. 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 scarcityof recurrent genetic changes even during relapse, pointing towards a relevant role of non-genetic sources of tumour heterogeneity. Compelling evidences suggest the existence of cells possessing 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 fundamental 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 cancer stem cells (NBcsc), with the ultimate goal of providing new molecular markers specific of these NBcsc and candidate genes that might result 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 population 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 relevant 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 receptors of the α-Neurexin (α-NRXN) family. To determine whether NXPH1/α–NRXNs activity is effectively 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 represent NBcsc markers. We identified the existence of a low subpopulation 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+ NBcells are endowed with a tumour-propagating capacity and that they are required to sustain tumour 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 markerp75NTR. Finally, we showed that inhibiting NXPH1 or α-NRXN1 activityabrogates NB tumour growth in xenograft models.
Our work provides the first experimental evidence that NXPH1,probably acting through its receptor α-NRXN1, exerts a functional role in NB progression. We suggest thatNXPH1, 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.
