RESUMEN
PURPOSE: Lung adenocarcinomas comprise the largest fraction of non-small cell lung cancer, which is the leading cause of cancer-related deaths. Seventy-five percent of adenocarcinomas lack targeted therapies because of scarcity of druggable drivers. Here, we classified tumors on the basis of signaling similarities and discovered subgroups within this unmet patient population. EXPERIMENTAL DESIGN: We leveraged transcriptional data from >800 early- and advanced-stage patients. RESULTS: We identified three robust subtypes dubbed mucinous, proliferative, and mesenchymal with respective pathway phenotypes. These transcriptional states lack discrete and causative mutational etiology as evidenced by similarly distributed oncogenic drivers, including KRAS and EGFR. The subtypes capture heterogeneity even among tumors lacking known oncogenic drivers. Paired multi-regional intratumoral biopsies demonstrated unified subtypes despite divergently evolved prooncogenic mutations, indicating subtype stability during selective pressure. Heterogeneity among in vitro and in vivo preclinical models is expounded by the human lung adenocarcinoma subtypes and can be leveraged to discover subtype-specific vulnerabilities. As proof of concept, we identified differential subtype response to MEK pathway inhibition in a chemical library screen of 89 lung cancer cell lines, which reproduces across model systems and a clinical trial. CONCLUSIONS: Our findings support forward translational relevance of transcriptional subtypes, where further exploration therein may improve lung adenocarcinoma treatment.See related commentary by Skoulidis, p. 913.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Biomarcadores de Tumor/genética , Neoplasias Pulmonares/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Animales , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Conjuntos de Datos como Asunto , Femenino , Heterogeneidad Genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , RNA-Seq , Transcriptoma/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The mechanisms by which MUC1 and p120 catenin contribute to progression of cancers from early transformation to metastasis are poorly understood. Here we show that p120 catenin ARM domains 1, 3-5, and 8 mediate interactions between p120 catenin and MUC1, and that these interactions modulate dynamic properties of cell adhesion, motility, and metastasis of pancreatic cancer cells. We also show that different isoforms of p120 catenin, when coexpressed with MUC1, create cells that exhibit distinct patterns of motility in culture (motility independent of cell adhesion, motility within a monolayer while exchanging contacts with other cells, and unified motility while maintaining static epithelial contacts) and patterns of metastasis. The results provide new insight into the dynamic interplay between cell adhesion and motility and the relationship of these to the metastatic process.
