RESUMEN
Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.
Asunto(s)
Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración , Transducción de Señal , Animales , Antineoplásicos/farmacología , Benzamidas , Carcinoma Neuroendocrino , Línea Celular Tumoral , Plasticidad de la Célula/efectos de los fármacos , Plasticidad de la Célula/fisiología , Resistencia a Antineoplásicos , Humanos , Masculino , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Nitrilos , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/fisiologíaRESUMEN
In spite of an initial clinical response to androgen deprivation therapy (ADT), the majority of prostate cancer patients eventually develop castration-resistant prostate cancer (CRPC). Recent studies have highlighted the role of epithelial plasticity, including transdifferentiation and epithelial-to-mesenchymal transition (EMT), in the development of AR pathway-negative CRPC, a form of the disease that has increased in incidence after the introduction of potent AR inhibitors. In this review, we will discuss the switches between different cell fates that occur in response to AR blockade or acquisition of specific oncogenic mutations, such as those in TP53 and RB1, during the evolution to CRPC. We highlight the urgent need to dissect the mechanistic underpinnings of these transitions and identify novel vulnerabilities that can be targeted therapeutically.
Asunto(s)
Evolución Clonal , Epitelio/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Plasticidad de la Célula , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Epitelio/patología , Humanos , Masculino , Células Madre Neoplásicas/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patologíaRESUMEN
This corrects the article DOI: 10.1038/ng.3889.
RESUMEN
The tumor suppressor P53 is a critical regulator of normal cellular homeostasis whose function is either distorted or lost in several cancer types including colorectal cancer (CRC). A small group of microRNAs have come to be recognized as essential mediators of P53 function. In a genome-wide systematic approach, we explored miRNAs that are substantially altered by P53 loss and found miR-30e to be the most significantly deregulated miRNA in P53-knockout human CRC cells. We identified miR-30e-5p to be a novel direct transcriptional target of P53 with gain and loss of function experiments revealing miR-30e-5p to be a significant regulator of tumor cell migration, invasion and in vivo metastasis mediated in part by integrins alpha-6 and beta-1 as novel targets. MiR-30e-5p also significantly reduced tumor cell proliferation by causing G1/S cell cycle arrest, which was achieved by inducing P21 and P27 expression. Finally, we found miR-30e-5p to be lost in resected CRC tumors as compared to normal colon tissues. Taken together, miR-30e-5p is a novel effector of P53-induced suppression of migration, invasion and metastasis.
Asunto(s)
Neoplasias Colorrectales/genética , Integrina alfa6/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , MicroARNs/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Adaptadoras Transductoras de Señales , Animales , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Ratones , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.