RESUMO
Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for 30% of mortality; however, mechanisms governing adaptation to the brain microenvironment remain poorly defined. We combine time-course RNA-sequencing of BCBM development with a Drosophila melanogaster genetic screen, and identify Rab11b as a functional mediator of metastatic adaptation. Proteomic analysis reveals that Rab11b controls the cell surface proteome, recycling proteins required for successful interaction with the microenvironment, including integrin ß1. Rab11b-mediated control of integrin ß1 surface expression allows efficient engagement with the brain ECM, activating mechanotransduction signaling to promote survival. Lipophilic statins prevent membrane association and activity of Rab11b, and we provide proof-of principle that these drugs prevent breast cancer adaptation to the brain microenvironment. Our results identify Rab11b-mediated recycling of integrin ß1 as regulating BCBM, and suggest that the recycleome, recycling-based control of the cell surface proteome, is a previously unknown driver of metastatic adaptation and outgrowth.
Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/patologia , Integrina beta1/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Humanos , Integrina beta1/genética , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Transporte Proteico , Transdução de Sinais , Microambiente Tumoral , Proteínas rab de Ligação ao GTP/genéticaRESUMO
Smokers' minimal exposure to nicotine replacement treatments (NRTs) may account for poor compliance and outcome with these treatments. This study tested effects of information versus sampling of NRTs on smokers' preferences and expectations. The study was a crossover comparing information-only (INF) with sampling (SMP) methods for five NRTs: gum (2 and 4 mg), lozenges (2 and 4 mg), and inhalers. Subjects were given computer-based presentations on NRTs (INF) and rated and ranked use variables (e.g., ease, sensory/ritual, perceived relief, embarrassment) and overall choice for "use to quit." After INF testing, subjects sampled each NRT (SMP) and again rated and ranked drugs. SMP was brief (4 min) to mimic potential use in practice. Results showed changes in perceptions and preferences post-SMP. NRT preferences shifted for overall "use to quit" (59%) and most use variables (43%-63%) post-SMP. Inhalers (generally top choice) showed a 20% drop in choice to quit (p<.04) and a 24% drop in anticipated "relief of withdrawal" (p<.04) post-SMP; 4-mg lozenge ratings increased for "relief of withdrawal" (p<.02). Ratings improved post-SMP for three of the five NRTs ("ease of use," p<.05) but were reduced overall for liking "sensory action" (p<.003) and reduced for all but 2-mg gum for "use to quit" (p<.03). Positive changes were seen in improved ratings of NRTs chosen post-SMP. Given that reactions to NRTs change with experience, sampling should allow for a more realistic choice of NRT (self-tailoring) and better compliance versus current trial-and-error methods.