Microwave ablation of primary breast cancer inhibits metastatic progression in model mice via activation of natural killer cells

Surgery is essential for controlling the symptoms and complications of stage IV breast cancer.However,locoregional treatment of primary tumors often results in distant progression,including lung metastasis,the most common type of visceral metastasis.As a minimally invasive thermal therapy,microwave ablation(MWA)has been attempted in the treatment of breast cancer,but the innate immune response after MWA has not yet been reported.Using two murine models of stage IV breast cancer,we found that MWA of primary breast cancer inhibited the progression of lung metastasis and improved survival.NK cells were activated after MWA of the primary tumor and exhibited enhanced cytotoxic functions,and the cytotoxic pathways of NK cells were activated.Depletion experiments showed that NK cells but not CD4+or CD8+T cells played a pivotal role in prolonging survival.Then,we found that compared with surgery or control treatment,MWA of the primary tumor induced completely different NK-cell-related cytokine profiles.Macrophages were activated after MWA of the primary tumor and produced IL-15 that activated NK cells to inhibit the progression of metastasis.In addition,MWA of human breast cancer stimulated an autologous NK-cell response.These results demonstrate that MWA of the primary tumor in metastatic breast cancer inhibits metastatic progression via the macrophage/IL-15/NK-cell axis.MWA of the primary tumor may be a promising treatment strategy for de novo stage IV breast cancer,although further substantiation is essential for clinical testing.

Crumbs proteins stabilize the cone mosaics of photoreceptors and improve vision in zebrafish

Although the unique organization of vertebrate cone mosaics was first described long ago,both their underlying molecular basis and physiological significance are largely unknown.Here,we demonstrate that Crumbs proteins,the key regulators of epithelial apical polarity,establish the planar cellular polarity of photoreceptors in zebrafish.Via heterophilic Crb2a-Crb2b interactions,the apicobasal polarity protein Crb2b restricts the asymmetric planar distribution of Crb2a in photoreceptors.The planar polarized Crumbs proteins thus balance intercellular adhesions and tension between photoreceptors,thereby stabilizing the geometric organization of cone mosaics.Notably,loss of Crb2b in zebrafish induces a nearsightedness-like phenotype in zebrafish accompanied by an elongated eye axis and impairs zebrafish visual perception for predation.These data reveal a detailed mechanism for cone mosaic homeostasis via previously undiscovered apical-planar polarity coordination and propose a pathogenic mechanism for nearsightedness.

WDR74 functions as a novel coactivator in TGF-β signaling

Smads are critical intracellular signal transducers for transforming growth factor-β(TGF-β) in mammalian cells. In this study, we have identified WD repeat-containing protein 74(WDR74) as a novel transcriptional coactivator for Smads in the canonical TGF-β signaling pathway. Through direct interactions with Smad proteins, WDR74 enhances TGF-β-mediated phosphorylation and nuclear accumulation of Smad2 and Smad3. Consequently, WDR74 enables stronger transcriptional responses and more robust TGF-β-induced physiological responses. Our findings have elucidated a critical role of WDR74 in regulating TGF-β signaling.