REGULATION OF HEPATIC POLYPLOIDY, REPROGRAMMING AND HEPATOCELLULAR CARCINOMA ALONG THE DIOXIN RECEPTOR ROUTE (Q3138680)
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Project Q3138680 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | REGULATION OF HEPATIC POLYPLOIDY, REPROGRAMMING AND HEPATOCELLULAR CARCINOMA ALONG THE DIOXIN RECEPTOR ROUTE |
Project Q3138680 in Spain |
Statements
222,640.0 Euro
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278,300.0 Euro
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80.0 percent
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1 January 2018
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31 December 2020
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UNIVERSIDAD DE EXTREMADURA
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06015
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EL CRECIMIENTO TUMORAL, LA RECIDIVA Y LA DISEMINACION METASTATICA ESTAN ASOCIADOS A FENOTIPOS CELULARES INDIFERENCIADOS, HACIENDO NECESARIA LA IDENTIFICACION Y CARACTERIZACION DE LOS REGULADORES MOLECULARES QUE INDUCEN Y MANTIENEN ESTADOS DIFERENCIADOS. LA MADURACION DEL HIGADO REQUIERE UN PROCESO DE DIFERENCIACION A UN ESTADO NO PROLIFERATIVO Y POLIPLOIDE QUE SE HA ASOCIADO RECIENTEMENTE AL DESARROLLO DE HEPATOCARCINOMA. ESTUDIOS DE NUESTRO Y DE OTROS LABORATORIOS INDICAN QUE EL RECEPTOR DE DIOXINA (AHR) ES UN REGULADOR DE LA DIFERENCIACION CELULAR, TANTO EN CONDICIONES HOMEOSTATICAS COMO EN DIFERENTES TIPOS TUMORALES INCLUYENDO HEPATOCARCINOMA, MELANOMA Y CARCINOMA EMBRIOIDE. LA CARACTERIZACION DE MODELOS MURINOS TRANSGENICOS EN LOS QUE SE HA SOBREEXPRESADO O ELIMINADO SU EXPRESION, INDICAN QUE AHR INHIBE PROLIFERACION Y METASTASIS DE CELULAS TUMORALES. ADICIONALMENTE, AHR PROMUEVE DIFERENCIACION CELULAR DURANTE EL DESARROLLO HEPATICO, CARDIACO, PULMONAR Y DEL SISTEMA INMUNE. NUESTRO LABORATORIO HA CONTRIBUIDO A LA IDENTIFICACION DE GENES DIANA DE AHR CONSIDERADOS RELEVANTES EN PLURIPOTENCIA Y REPROGRAMACION CELULAR Y CUYA DESREGULACION ALTERA LA REGENERACION HEPATICA Y EL DESARROLLO DE CANCER HEPATICO EN RATONES NULOS (AHR-/-) PARA ESTE RECEPTOR. MAS AUN, AHR CONTRIBUYE AL ESTABLECIMIENTO DEL FENOTIPO POLIPLOIDE NECESARIO PARA UNA CORRECTA MADURACION HEPATICA, Y LLEVA A CABO DICHA FUNCION MODULANDO RUTAS QUE REGULAN PROLIFERACION, DIFERENCIACION Y METABOLISMO. ESTA PROPUESTA PARTE DE LAS SIGUIENTES OBSERVACIONES PREVIAS: (I) AHR REPRIME LA EXPRESION DE GENES QUE INDUCEN UN FENOTIPO INDIFERENCIADO Y PLURIPOTENTE EN MODELOS CELULARES DE HEPATOCARCINOMA, MELANOMA Y TERATOMA; (II) LA REGENERACION DE LESIONES HEPATICAS Y PULMONARES SE VE POTENCIADA Y ES MAS EFICIENTE EN RATONES AHR-/-, Y DICHA RESPUESTA IMPLICA LA EXPANSION DE SUBPOBLACIONES BASALES DE CELULAS INDIFERENCIADAS; (III) AHR INHIBE EL DESARROLLO Y LA PROGRESION DE HEPATOCARCINOMA EN UN MODELO EXPERIMENTAL MURINO; (IV) LA ACTIVACION DE LOS GENES DE REPROGRAMACION CELULAR KLF4-SOX2-OCT4-MYC (KSOM) EN FONDO GENETICO AHR-/- INCREMENTA LA SENSIBILIDAD AL DESARROLLO DE TERATOMAS INDIFERENCIADOS; (V) AHR MODULA DIFERENCIACION HEPATICA Y POLIPLOIDIA REGULANDO LAS VIAS INS-R/PI3K/AKT/MTOR, ERK1/2 Y WNT/BETA-CATENINA; (VI) LA EXPRESION DE AHR SE VE ALTERADA EN HEPATOCARCINOMA HUMANO CON RESPECTO AL TEJIDO TUMORAL ADYACENTE DEL MISMO PACIENTE. EN ESTE PROYECTO NOS PLANTEAMOS LOS OBJETIVOS SIGUIENTES: (1) DETERMINAR MOLECULARMENTE COMO SE LLEVA A CABO LA INTERACCION DE AHR CON LAS RUTAS ANTES MENCIONADAS QUE REGULAN EL BALANCE ENTRE PROLIFERACION, DIFERENCIACION Y POLIPLOIDIA EN HEPATOCITOS PRIMARIOS Y EN TUMORES HEPATICOS GENERADOS EN MODELOS ANIMALES, Y VALIDAR LOS RESULTADOS ESPERABLES EN HEPATOCARCINOMA HUMANO; (2) INVESTIGAR LA CONTRIBUCION DE AHR A LA REPROGRAMACION EN CULTIVO E IN VIVO DE HEPATOCITOS REPROGRAMABLES PROCEDENTES DE RATONES KSOM Y DETERMINAR LA CAPACIDAD DE CELULAS MADRE Y DE HEPATOCITOS PRIMARIOS AHR+/+ Y AHR-/- PARA POTENCIAR LA REGENERACION HEPATICA TRAS HEPATECTOMIA PARCIAL Y (3) GENERAR Y CARACTERIZAR MOLECULARMENTE SOBRE LA BASE DE LAS RUTAS ANTERIORMENTE MENCIONADAS MODELOS DE HEPATOCARCINOMA MURINO INDUCIBLES POR ACTIVACION DEL ONCOGEN KRASG12D+/CRE EN FONDO AHR+/+ Y AHR-/- Y MODELOS PDX (PATIENT DERIVED XENOGRAFT) A PARTIR DE BIOPSIAS DE HEPATOCARCINOMA HUMANO. ESTOS MODELOS SERAN TRATADOS CON LIGANDOS DE AHR EN PRESENCIA/AUSENCIA DE SORAFENIB. (Spanish)
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TUMOR GROWTH, RECURRENCE AND METASTATIC DISEMINATION ARE LINKED TO UNDIFFERENTIATED CELL PHENOTYPES MAKING NECCESARY THE IDENTIFICATION AND CHARACTERIZATION OF MOLECULAR REGULATORS THAT INDUCE AND MAINTAIN DIFFERENTIATION. THE LIVER IS A MAJOR ORGAN WHERE MATURATION REQUIRES DIFFERENTIATION TO A NON-PROLIFERATIVE POLYPLOID STATUS THAT RECENT STUDIES HAD ASSOCIATED TO INCREASED HEPATOCELLULAR CARCINOMA SUSCEPTIBILITY. WORK FROM OUR GROUP AND FROM OTHERS HAVE SHOWN THAT THE DIOXIN RECEPTOR (AHR) REGULATES CELL DIFFERENTIATION UNDER PHYSIOLOGICAL CONDITIONS AND IN SUCH TUMORS AS HEPATOCELLULAR CARCINOMA, MELANOMA AND EMBRYOID CARCINOMA. THE CHARACTERIZATION OF MURINE TRANSGENIC MODELS IN WHICH AHR HAS BEEN OVEREXPRESSED OR KNOCKED-OUT REVEALS THAT AHR INHIBITS PROLIFERATION AND TUMOR CELL METASTASIS. IN ADDITION, AHR PROMOTES CELL DIFFERENTIATION DURING LIVER, HEART, LUNG AND IMMUNE SYSTEM DEVELOPMENT. OUR LABORATORY HAS MADE SIGNIFICANT CONTRIBUTIONS TO THE IDENTIFICATION OF AHR TARGET GENES CONSIDERED RELEVANT FOR PLURIPOTENCY AND CELLULAR REPROGRAMMING, AND WHOSE MISSREGULATION ALTERS LIVER REGENERATION AND THE DEVELOPMENT OF LIVER TUMORS IN AHR-NULL (AHR-/-) MICE. FURTHERMORE, AHR IS INVOLVED IN STABLISHING THE POLYPLOID PHENOTYPE NEEDED FOR LIVER MATURATION, AND IT DOES SO BY REGULATING SIGNALING PATHWAYS CONTROLLING PROLIFERATION, DIFFERENTIATION AND METABOLISM. THIS PROPOSAL IS BASED ON THE FOLLOWING PREVIOUS OBSERVATIONS: (I) AHR REPRESSES THE EXPRESSION OF GENES RESPONSIBLE FOR UNDIFFERENTIATION AND PLURIPOTENCY IN CELLULAR MODELS OF HEPATOCELLULAR CARCINOMA, MELANOMA AND TERATOMA; (II) REGENERATION OF LIVER AND LUNG LESIONS IS ENHANCED AND TAKES PLACE MORE EFFICIENTLY IN AHR-/- MICE, AND SUCH RESPONSE INVOLVES THE EXPANSION OF UNDIFFERENTIATED BASAL CELL SUBPOPULATIONS; (III) AHR INHIBITS HEPATOCELLULAR CARCINOMA PROGRESSION IN A MURINE EXPERIMENTAL MODEL; (IV) ACTIVATION OF REPROGRAMMING GENES KLF4-SOX2-OCT4-MYC (KSOM) IN AHR-/- GENETIC BACKGROUND INCREASES SENSITIVITY TO UNDIFFERENTIATED TERATOMA FORMATION; (V) AHR MODULATES HEPATIC DIFFERENTIATION AND POLYPLOIDY BY THE INS-R/PI3K/AKT/MTOR, ERK1/2 Y WNT/BETA-CATENINA SIGNALING PATHWAYS; (VI) AHR EXPRESSION IS ALTERED IN HUMAN HEPATOCARCINOMA AS COMPARED TO NON-TUMORAL SURROUNDING TISSUE FROM THE SAME PATIENT. THIS STUDY HAS THE FOLLOWING SPECIFIC OBJECTIVES: (1) TO CHARACTERIZE AT THE MOLECULAR LEVEL HOW AHR INTERACTS WITH THE SIGNALING PATHWAYS INDICATED ABOVE THAT REGULATE THE BALANCE BETWEEN PROLIFERATION, DIFFERENTIATION AND POLYPLOIDY IN PRIMARY HEPATOCYTES AND MURINE LIVER TUMORS AND TO VALIDATE THE EXPECTED RESULTS IN HUMAN HEPATOCARCINOMAS; (2) TO INVESTIGATE THE CONTRIBUTION OF AHR TO IN VITRO AND IN VIVO REPROGRAMMING OF PRIMARY HEPATOCYTES OBTAINED FROM REPROGRAMMABLE KSOM MICE AND TO DETERMINE THE POTENTIAL OF LIVER STEM CELLS AND PRIMARY HEPATOCYTES FROM AHR+/+ AND AHR-/- MICE TO INDUCE LIVER REGENERATION AFTER PARTIAL HEPATECTOMY AND (3) TO GENERATE AND TO CHARACTERIZE, WITH RESPECT TO THE PATHWAY MENTIONED ABOVE, A NOVEL MODEL OF HEPATOCELLULAR CARCINOMA PRODUCED BY THE INDUCIBLE EXPRESSION OF THE KRASG12D+/CRE ONCOGEN IN AHR+/+ AND AHR-/- GENETIC BACKGROUND AND TO ESTABLISH PDX (PATIENT-DERIVED XENOGRAFT) MODELS FROM HUMAN HEPATOCARCINOMA BIOPSIES. THIS MODELS WILL BE TREATED WITH AHR LIGANDS IN PRESENCE/ABSENCE OF SORAFENIB. (English)
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Badajoz
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Identifiers
SAF2017-82597-R
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