RESUMEN
Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.
Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma Basocelular/genética , Glándulas Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/genética , Transcriptoma , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Fibroblastos Asociados al Cáncer/patología , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patología , Linaje de la Célula/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Cadena alfa 1 del Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Glándulas Mamarias Animales/patología , Glándulas Mamarias Animales/virología , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Virus del Tumor Mamario del Ratón/crecimiento & desarrollo , Virus del Tumor Mamario del Ratón/patogenicidad , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Ratones , Metástasis de la Neoplasia , Embarazo , Análisis de la Célula Individual , Microambiente Tumoral/genéticaRESUMEN
Microtubule-associated serine/threonine kinase-like (MASTL; Greatwall) is a well-characterized kinase, whose catalytic role has been extensively studied in relation to cell-cycle acceleration. Importantly, MASTL has been implicated to play a substantial role in cancer progression and subsequent studies have shown that MASTL is a significant regulator of the cellular actomyosin cytoskeleton. Several kinases have non-catalytic properties, which are essential or even sufficient for their functions. Likewise, MASTL functions have been attributed both to kinase-dependent phosphorylation of downstream substrates, but also to kinase-independent regulation of the actomyosin contractile machinery. In this review, we aimed to highlight the catalytic and non-catalytic roles of MASTL in proliferation, migration, and invasion. Further, we discussed the implications of this dual role for therapeutic design.