Untitled - Red TemÃ¡tica de investigaciÃ³n cooperativa en cÃ¡ncer

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P-26 SECUENCIACIÓN DE ALTO RENDIMIENTO PARA LA CARACTERIZACIÓN DEL MIRNAOMA EN CPNM EN ESTADIOS INICIALES. ANÁLISIS DE EXPRE- SIÓN DIFERENCIAL GALLACH S 1 , JANTUS-LEWINTRE E 1 , USÓ M 1 , FIGUEROA S 1 , MONTANER D 2 , MARTINEZ CHAN N 1 , HERNANDO C 1 , CAMPS C 1 1 HOSPITAL GENERAL UNIVERSITARIO DE VALENCIA, VALENCIA (RD06/0020/1024) 2 CENTRO INVESTIGACIÓN PRÍNCIPE FELIPE, VALENCIA Introducción: Los miRNAs están siendo estudiados como posibles biomarcadores en cáncer. La secuenciación masiva es una herramienta útil para estudiar el miRNAoma en tumores sólidos, por lo que utilizamos secuenciación de alto rendimiento (NGS), para estudiar la expresión de miRNAs en una cohorte de pacientes con CPNM en estadios tempranos (tejido pulmonar tumoral vs normal). Materiales y métodos: Se secuenciaron por NGS (plataforma SOLiD) en multiplex muestras de RNA de 35 pacientes (tejido tumoral y normal) con un RIN ≥ 8, enriquecidas en la fracción de miRNAs. Los datos fueron normalizados y las secuencias se compararon con bases de datos de miRNAs maduros y no maduros. Para el análisis funcional se usaron las bases de datos, Gene Ontology (GO) y KEGG. Resultados: La secuenciación usando marcaje de códigos de barras multiplexado, de 35 muestras de miRNAs pareadas (tumor vs tejido normal) resultó en un total de 1268 miRNAs (maduros y no maduros) detectados en al menos una muestra. Se encontraron 33 miRNAs sobreexpresados y 17 infraexpresados de manera significativa en las muestras tumorales frente a parénquima pulmonar normal. El análisis funcional reveló diferencias significativas en 7 vías KEGG y en 400 procesos biológicos (PB) de acuerdo con GO. Al comparar las histología adenocarcinoma vs escamosa hubo diferencias significativas en 19 vías KEGG y 144 PB algunos de ellos relacionados con la angiogénesis y regulación de VEGF. Conclusiones: La técnica utilizada para la expresión diferencial de miRNAs es una tecnología útil y novedosa para la caracterización del miRNAome. El uso de códigos de barras multiplexado permite reducir el coste por muestra. Varios miRNAs fueron expresados diferencialmente entre tejido tumoral frente al normal. Los ensayos de validación están en proceso. P-27 ISOLATION AND CHARACTERISATION OF RHABDOMYOSARCOMA-INITIA- TING CELLS ALMAZÁN-MOGA A 1 , ROMA J 1 , MOLIST C 1 , REVENTÓS J 2 , SÁNCHEZ DE TOLEDO J 1 , GALLEGO S 1 1 PEDIATRIC ONCOLOGY AND HEMATOLOGY UNIT, HOSPITAL UNIVERSITARI VALL D’HEBRON, UNIVER SITAT AUTÒNOMA DE BARCELONA, BARCELONA (RD06/0020/1021) 2 RESEARCH UNIT IN BIOMEDICINE AND TRANSLATIONAL AND PAEDIATRIC ONCOLOGY, VALL D’HEBRON INSTITUT DE RECERCA (VHIR), UNIVERSITAT AUTÒNOMA DE BARCELONA, BARCELONA (RD06/0020/0058) Background: Rhabdomyosarcoma (RMS) is a malignant tumour originating from skeletal muscle myoblastic precursors. Current treatment protocols yield overall survival of 60-65%. Recently, growing evidence supporting the existence of tumour-initiating cells (TICs) in a wide range of cancers has been accumulated. These cells are thought to be the only cells able to initiate primary tumours, produce metastases and survive conventional therapies. Recent publications have suggested that RMS follows the cancer stem cell model. For this reason, the design of therapies specifically targeting this subpopulation, in a primary tumour or in blood circulating tumour cells, may considerably reduce the probability of metastases and relapses in RMS patients. Objectives: To isolate and molecularly characterise the TICs subpopulation in RMS cell lines, primary tumours and circulating RMS cells to achieve a significant pharmacological inhibition of the most significant signalling pathways for TIC maintenance. Methods: Spheres and holoclone assays were used to enrich and isolate TICs in RMS cell lines. Real-time PCR and Western blot were used to determine activated signalling pathways in this subpopulation. Gamma-secretase inhibitors (DAPT and GSI XXI) and Vismodegib were used to inhibit Notch and Hedgehog pathways, respectively. Results: RMS cell lines formed spheres and holoclones which showed an upregulation of Notch and Hedgehog pathways. Pharmacological inhibition of both pathways reduced the ability of RMS cell lines to form spheres and holoclones, which suggests that these pathways play an important role in the maintenance of putative RMS-initiating cells. Conclusions: Our in vitro results point to Notch and Hedgehog pathways as therapeutic targets against RMS-initiating cells, thereby indicating that their pharmacological inhibitors may improve RMS patients survival, especially in high-risk and recurrent cases. 70 71
P-28 EFFECTS OF GAMMA-SECRETASE INHIBITORS IN RHABDOMYOSARCOMA MOUSE MODELS MOLIST C 1 , ALMAZÁN-MOGA A 1 , ROMA J 1 , GARCIA M 2 , DOLL A 2 , REVENTÓS J 2 , SÁNCHEZ DE TOLEDO J 1 , GALLEGO S 1 1 PEDIATRIC ONCOLOGY AND HEMATOLOGY UNIT, HOSPITAL UNIVERSITARI VALL D’HEBRON, UNIVER SITAT AUTÒNOMA DE BARCELONA, BARCELONA (RD06/0020/1021) 2 RESEARCH UNIT IN BIOMEDICINE AND TRANSLATIONAL AND PAEDIATRIC ONCOLOGY, VALL D’HEBRON INSTITUT DE RECERCA (VHIR), UNIVERSITAT AUTÒNOMA DE BARCELONA, BARCELONA (RD06/0020/0058) Background: Rhabdomyosarcoma (RMS) is a malignant tumour derived from myoblastic precursors of skeletal muscle. It is a rare disease with an incidence of 5.3 cases/million/ year affecting mainly children under 15 years old. Current treatments include chemotherapy, surgeryand radiotherapy, with 5-year overall survival of 60-65%. Our previous in vitro studies suggest that inhibition of the NOTCH pathway bygamma-secretase inhibitors produces a significant decrease in invasiveness of RMS cell lines in culture. Moreover, NOTCH pathway activation seems to play a crucial role in the activation of the N-Cadherin. Objectives: To establish the animal models and to ascertain theeffects of NOTCH pathway inhibition using murine xenograft models of RMS in an attempt to find new molecular targets for treatingpatients with RMS. Methods: Intramuscular and intravenous injection of RH-30 RMS cells into SCID mice and treatment with NOTCHpathway inhibitors. Results: Primary RMS tumours showed a reduction in size when treated with the gammasecretase inhibitor DAPT.Currently, the model of metastasis (by intravenous injection of RH-30 RMS cells) is under development. Discussion: The characterization of the NOTCH pathway in RMS murine xenografts in combination with the use of NOTCH pathway inhibitors may lead to noveltherapeutic strategies for children with high risk or recurrent rhabdomyosarcoma. We hypothesize that the use of specific NOTCH pathwayinhibitors in vivo, in a xenograft mouse model of RMS, could lead to new co-adjuvant treatments for patients with metastatic disease orhigh risk of developing metastasis. P-29 MOLECULAR EVENTS IN ENDOMETRIAL CARCINOSARCOMAS AND THE ROLE OF HMGA2 IN ENDOMETRIAL CARCINOGENESIS ROMERO-PÉREZ L 1 , CASTILLA MA 1 , DÍAZ-MARTÍN J 1 , MORENO-BUENO G 2 , PALACIOS CALVO J 3 1 INSTITUTO DE BIOMEDICINA DE SEVILLA (IBIS), SEVILLA (RD06/0020/0013) 2 INSTITUTO DE INVESTIGACIONES BIOMÉDICAS “ALBERTO SOLS”-UAM ”/ FUND.MD ANDERSON CANCER CENTRE, MADRID 3 HHUU VIRGEN DEL ROCÍO-IBIS/ HHUU RAMÓN Y CAJAL, MADRID (RD06/0020/0013) The molecular events implicated in the development of endometrial carcinosarcoma (ECS) remain poorly understood. Using cDNA microarrays, we analyzed a group of 15 ECSs and compared their gene expression profiles with those obtained from a group of 23endometrioid endometrial carcinomas (EECs). We demonstrated changes in the expression of genes modulating processes such as the epithelial-mesenchymal transition (EMT), muscle differentiation, the expression of cancer/ testis antigens (CTAs) and immune response in ECSs. The HMGA2 gene (High Mobility Group AT-hook 2) is an embryonic nuclear factor that mediates EMT in various tumor models and it was among the genes overexpressed in ECSs. HMGA2 overexpression was confirmed in 54% of ECSs by qRT-PCR and immunohistochemistry. Moreover, we found a significant inverse correlation between the expression of HMGA2 and let-7b, a member ofthe let-7 family of miRNAs that represses HMGA2 expression. These changes were also associated with overexpression of Lin28B, a suppressor of microRNA biogenesis that is implicated in cancer progression and metastasis. Finally, HMGA2 overexpression, which was detected in less than 3% of EECs, was observed in many non-endometrioid carcinomas (NEECs) (46% of 28 samples). This pattern of expression, restricted to NEECs and ECSs, reflects a role for HMGA2 in endometrial carcinogenesis that is associated with aggressive phenotypes, and points to its potential use as a marker to distinguish between endometrioid and non-endometrioid tumors. * This study was performed in collaboration with Xavier Matias-Guiu (HHUU Arnau de Vilanova, IRBLLEIDA, Lleida. RD06/0020/0134) and Jaime Prat (Hospital Sant Pau, Barcelona. RD06/0020/0015) 72 73
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