RESUMO
Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is known to function as a molecular chaperone, particularly for desmin, but also interacts with a wide variety of additional proteins. The molecular chaperone function is also enhanced by signal-dependent phosphorylation at specific residues under stress conditions. Naturally occurring mutations in CRYAB, the gene that encodes alpha-B-crystallin, have been suggested to alter ionic intermolecular interactions that affect dimerization and chaperone function. These mutations have been associated with myofibrillar myopathy, restrictive cardiomyopathy, and hypertrophic cardiomyopathy and promote pathological hypertrophy through different mechanisms such as desmin aggregation, increased reductive stress, or activation of calcineurin-NFAT signaling. This review will discuss the known mechanisms by which alpha-B-crystallin functions in cardiac homeostasis and the pathogenesis of cardiomyopathies and provide insight into potential future areas of exploration.
Assuntos
Cardiomiopatias , Cardiomiopatia Restritiva , Humanos , Desmina/genética , Cardiomiopatias/patologia , Mutação , Cardiomiopatia Restritiva/complicações , Chaperonas Moleculares/genéticaRESUMO
Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.
Assuntos
Ensaios de Seleção de Medicamentos Antitumorais , Imunoterapia , Melanoma/patologia , Melanoma/terapia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno CTLA-4/imunologia , Células Cultivadas , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Heterogeneidade Genética , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Melanoma/diagnóstico , Melanoma/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , RNA-Seq , Resultado do Tratamento , Sequenciamento Completo do GenomaRESUMO
The study by Bok and colleagues in this issue introduces a new paradigm for generating new mouse models for melanoma research. Genetically engineered mouse models (GEMM) have been crucial for understanding tumor initiation and modeling potential therapies, but are time consuming to create. Bok and colleagues generated and validated high-contribution chimeric GEMM models using common melanoma GEMMs as a starting point and added additional CRISPR, Cre-inducible, and Dox-inducible alleles. This rapid method for generating new models has the potential to revolutionize mouse modeling for melanoma.See related article by Bok et al., p. 912.
