RESUMEN
Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-ß ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/fisiopatología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias Encefálicas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Línea Celular Tumoral , Femenino , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Trasplante de Neoplasias , Estudios Prospectivos , Proteoglicanos/genética , Proteoglicanos/metabolismo , Interferencia de ARN , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismoRESUMEN
In Saccharomyces cerevisiae and HeLa cells, the NoCut checkpoint, which involves the chromosome passenger kinase Aurora B, delays the completion of cytokinesis in response to anaphase defects. However, how NoCut monitors anaphase progression has not been clear. Here, we show that retention of chromatin in the plane of cleavage is sufficient to trigger NoCut, provided that Aurora/Ipl1 localizes properly to the spindle midzone, and that the ADA histone acetyltransferase complex is intact. Furthermore, forcing Aurora onto chromatin was sufficient to activate NoCut independently of anaphase defects. These findings provide the first evidence that NoCut is triggered by the interaction of acetylated chromatin with the passenger complex at the spindle midzone.