RESUMEN
Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.
Asunto(s)
Adenocarcinoma/genética , Carcinoma Neuroendocrino/genética , Regulación Neoplásica de la Expresión Génica , Próstata/metabolismo , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Adenocarcinoma/metabolismo , Animales , Carcinoma Neuroendocrino/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Técnicas de Cultivo de Órganos/métodos , Pronóstico , Próstata/patología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismoRESUMEN
Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration resistant prostate cancers become androgen receptor (AR) signaling-independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome and interactome using in vivo, in vitro and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR-co-factors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for EZH2 inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights on how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage-specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.
Asunto(s)
Linaje de la Célula , Epigénesis Genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata/metabolismo , Animales , Línea Celular Tumoral , Plasticidad de la Célula , ADN/química , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Transgénicos , Proteína Proto-Oncogénica N-Myc/genética , Trasplante de Neoplasias , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Transducción de Señal , TranscriptomaRESUMEN
Positional cloning in maize (Zea mays) requires development of markers in the region of interest. We found that primers designed to amplify annotated insertion-deletion polymorphisms of seven base pairs or greater between B73 and Mo17 produce polymorphic markers at a 97% frequency with 49% of the products showing co-dominant fragment length polymorphisms. When the same polymorphisms are used to develop markers for B73 and W22 or Mo17 and W22 mapping populations, 22% and 31% of markers are co-dominant, respectively. There are 38,223 Indel polymorphisms that can be converted to markers providing high-density coverage throughout the maize genome. This strategy significantly increases the efficiency of marker development for fine-mapping in maize.