RESUMO
In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin ß1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages.
Assuntos
Ácidos Graxos , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Humanos , Feminino , Ácidos Graxos/metabolismo , Camundongos , Linhagem Celular Tumoral , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Metástase NeoplásicaRESUMO
The utilization of single-cell resolved spatial transcriptomics to delineate immune responses during SARS-CoV-2 infection was able to identify M1 macrophages to have elevated expression of IFI27 in areas of infection.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Perfilação da Expressão Gênica , Macrófagos , Proteínas de MembranaRESUMO
Complex I (NADH:ubiquinone oxidoreductase) is central to cellular NAD(+) recycling and accounts for approximately 40% of mitochondrial ATP production. To understand how complex I function impacts respiration and plant development, we isolated Arabidopsis (Arabidopsis thaliana) lines that lack complex I activity due to the absence of the catalytic subunit NDUFV1 (for NADH:ubiquinone oxidoreductase flavoprotein1) and compared these plants with ndufs4 (for NADH:ubiquinone oxidoreductase Fe-S protein4) mutants possessing trace amounts of complex I. Unlike ndufs4 plants, ndufv1 lines were largely unable to establish seedlings in the absence of externally supplied sucrose. Measurements of mitochondrial respiration and ATP synthesis revealed that compared with ndufv1, the complex I amounts retained by ndufs4 did not increase mitochondrial respiration and oxidative phosphorylation capacities. No major differences were seen in the mitochondrial proteomes, cellular metabolomes, or transcriptomes between ndufv1 and ndufs4. The analysis of fluxes through the respiratory pathway revealed that in ndufv1, fluxes through glycolysis and the tricarboxylic acid cycle were dramatically increased compared with ndufs4, which showed near wild-type-like fluxes. This indicates that the strong growth defects seen for plants lacking complex I originate from a switch in the metabolic mode of mitochondria and an up-regulation of respiratory fluxes. Partial reversion of these phenotypes when traces of active complex I are present suggests that complex I is essential for plant development and likely acts as a negative regulator of respiratory fluxes.
Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Complexo I de Transporte de Elétrons/genética , Mitocôndrias/genética , Mutação , Trifosfato de Adenosina/metabolismo , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/metabolismo , Eletroforese em Gel de Poliacrilamida , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Mitocôndrias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Consumo de Oxigênio , Fenótipo , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Plântula/genética , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Regulação para CimaRESUMO
Gas chromatography-mass spectrometry (GC-MS) profiles were generated from U87 glioma cells and human mesenchymal stem cells (hMSC). 37 metabolites representing glycolysis intermediates, TCA cycle metabolites, amino acids and lipids were selected for a detailed analysis. The concentrations of these metabolites were compared and Pearson correlation coefficients were used to calculate the relationship between pairs of metabolites. Metabolite profiles and correlation patterns differ significantly between the two cell lines. These profiles can be considered as a signature of the underlying biochemical system and provide snap-shots of the metabolism in mesenchymal stem cells and tumor cells.