RESUMEN
Breast cancer development is associated with increasing tissue stiffness over years. To more accurately mimic the onset of gradual matrix stiffening, which is not feasible with conventional static hydrogels, mammary epithelial cells (MECs) were cultured on methacrylated hyaluronic acid hydrogels whose stiffness can be dynamically modulated from "normal" (<150 Pascals) to "malignant" (>3,000 Pascals) via two-stage polymerization. MECs form and remain as spheroids, but begin to lose epithelial characteristics and gain mesenchymal morphology upon matrix stiffening. However, both the degree of matrix stiffening and culture time before stiffening play important roles in regulating this conversion as, in both cases, a subset of mammary spheroids remained insensitive to local matrix stiffness. This conversion depended neither on colony size nor cell density, and MECs did not exhibit "memory" of prior niche when serially cultured through cycles of compliant and stiff matrices. Instead, the transcription factor Twist1, transforming growth factor ß (TGFß), and YAP activation appeared to modulate stiffness-mediated signaling; when stiffness-mediated signals were blocked, collective MEC phenotypes were reduced in favor of single MECs migrating away from spheroids. These data indicate a more complex interplay of time-dependent stiffness signaling, spheroid structure, and soluble cues that regulates MEC plasticity than suggested by previous models.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias de la Mama/genética , Mecanotransducción Celular/genética , Fosfoproteínas/genética , Factor de Crecimiento Transformador beta/genética , Proteína 1 Relacionada con Twist/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Células Epiteliales/metabolismo , Células Epiteliales/patología , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Hidrogeles/química , Comunicación Paracrina/genética , Transducción de Señal/genética , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
Tumors are composed of heterogeneous phenotypes, each having different sensitivities to the microenvironment. One microenvironment characteristic - matrix stiffness - helps to regulate malignant transformation and invasion in mammary tumors, but its influence on oral squamous cell carcinoma (OSCC) is unclear. We observed that, on stiff matrices, a highly invasive OSCC cell line (SCC25) comprising a low E-cad to N-cad ratio (InvH/E:NL; SCC25) had increased migration velocity and decreased adhesion strength compared to a less invasive OSCC cell line (Cal27) with high E-cad to N-cad ratio (InvL/E:NH; Cal27). However, InvL/E:NH cells acquire a mesenchymal signature and begin to migrate faster when exposed to prolonged time on a stiff niche, suggesting that cells can be mechanically conditioned. Owing to increased focal adhesion assembly, InvL/E:NH cells migrated faster, which could be reduced when increasing integrin affinity with high divalent cation concentrations. Mirroring these data in human patients, we observed that collagen organization, an indicator of matrix stiffness, was increased with advanced disease and correlated with early recurrence. Consistent with epithelial tumors, our data suggest that OSCC cells are mechanically sensitive and that their contribution to tumor progression is mediated in part by this sensitivity.This article has an associated First Person interview with the first author of the paper.
Asunto(s)
Carcinoma de Células Escamosas/patología , Movimiento Celular , Transformación Celular Neoplásica/patología , Colágeno/metabolismo , Transición Epitelial-Mesenquimal , Matriz Extracelular/patología , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/metabolismo , Adhesión Celular , Transformación Celular Neoplásica/metabolismo , Matriz Extracelular/metabolismo , Humanos , Neoplasias de la Boca/metabolismo , Células Tumorales Cultivadas , Microambiente TumoralRESUMEN
The use of biomaterials has substantially contributed to both our understanding of tumorigenesis and our ability to identify and capture tumour cells in vitro and in vivo. Natural and synthetic biomaterials can be applied as models to recapitulate key features of the tumour microenvironment in vitro, including architectural, mechanical and biological functions. Engineered biomaterials can further mimic the spatial and temporal properties of the surrounding tumour niche to investigate the specific effects of the environment on disease progression, offering an alternative to animal models for the testing of cancer cell behaviour. Biomaterials can also be used to capture and detect cancer cells in vitro and in vivo to monitor tumour progression. In this Review, we discuss the natural and synthetic biomaterials that can be used to recreate specific features of tumour microenvironments. We examine how biomaterials can be applied to capture circulating tumour cells in blood samples for the early detection of metastasis. We highlight biomaterial-based strategies to investigate local regions adjacent to the tumour and survey potential applications of biomaterial-based devices for diagnosis and prognosis, such as the detection of cellular deformability and the non-invasive surveillance of tumour-adjacent stroma.