Divide and conquer: two stem cell populations in squamous epithelia, reserves and the active duty forces

Stem cells are of great interest to the scientific community due to their potential role in regenerative and rejuvenative medicine.However,their role in the aging process and carcinogenesis remains unclear.Because DNA replication in stem cells may contribute to the background mutation rate and thereby to cancer,reducing proliferation and establishing a relatively quiescent stem cell compartment has been hypothesized to limit DNA replication-associated mutagenesis.On the other hand,as the main function of stem cells is to provide daughter cells to build and maintain tissues,the idea of a quiescent stem cell compartment appears counterintuitive.Intriguing observations in mice have led to the idea of separated stem cell compartments that consist of cells with different proliferative activity.Some epithelia of short-lived rodents appear to lack quiescent stem cells.Comparing stem cells of different species and different organs(comparative stem cell biology)may allow us to elucidate the evolutionary pressures such as the balance between cancer and longevity that govern stem cell biology(evolutionary stem cell biology).The oral mucosa and its stem cells are an exciting model system to explore the characteristics of quiescent stem cells that have eluded biologists for decades.

The β-catenin/YAP signaling axis is a key regulator of melanoma-associated fibroblasts

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.