摘要
β-catenin is a multifunctional protein that plays crucial roles in embryonic development,physiological homeostasis,and a wide variety of human cancers.Previously,we showed that in vivo targeted ablation ofβ-catenin in melanoma-associated fibroblasts after melanoma formation significantly suppressed tumor growth.However,when the expression ofβ-catenin was ablated in melanoma-associated fibroblasts before tumor initiation,melanoma development was surprisingly accelerated.How stromalβ-catenin deficiency leads to opposite biological effects in melanoma progression is not completely understood.Here,we report thatβ-catenin is indispensable for the activation of primary human stromal fibroblasts and the mediation of fibroblast-melanoma cell interactions.Using coimmunoprecipitation and proximity ligation assays,we identified Yes-associated protein(YAP)as an importantβ-catenin-interacting partner in stromal fibroblasts.YAP is highly expressed in the nuclei of cancer-associated fibroblasts(CAFs)in both human and murine melanomas.Mechanistic investigation revealed that YAP nuclear translocation is significantly modulated by Wnt/β-catenin activity in fibroblasts.Blocking Wnt/β-catenin signaling in stromal fibroblasts inhibited YAP nuclear translocation.In the absence of YAP,the ability of stromal fibroblasts to remodel the extracellular matrix(ECM)was inhibited,which is consistent with the phenotype observed in cells withβ-catenin deficiency.Further studies showed that the expression of ECM proteins and enzymes required for remodeling the ECM was suppressed in stromal fibroblasts after YAP ablation.Collectively,our data provide a new paradigm in which theβ-catenin-YAP signaling axis regulates the activation and tumor-promoting function of stromal fibroblasts.
基金
This work was supported by NIH R15CA228014(YZ),the Cincinnati Cancer Center-Mentor-Mentee Award(YZ),the Harry J Lloyd Trust Research Award(Y.Z.)and the CCTST Pilot Translational Research&Innovative Core Grant(Y.Z.).
