VPS35/Retromer-dependent MT1-MMP regulation confers melanoma metastasis

Retromer is a conserved endosomal trafficking complex responsible for recycling transmembrane protein cargoes. Membrane-type I matrix metalloproteinase (MT1-MMP), a well-studied membrane-type metalloprotease, is highly expressed in metastatic melanomas. Previously, we reported that inducing MT1-MMP perinuclear localization and inhibiting MT1-MMP membrane localization significantly reduce melanoma metastasis. However, the regulation of MT1-MMP subcellular localization and recycling is still largely unknown. Here, we performed target gene shRNA screening and found that shRNA targeting the Retromer complex subunit vacuolar protein sorting 35 (VPS35) inhibited MT1-MMP membrane localization and induced its perinuclear localization. We found that inhibiting VPS35/Retromer decreased MT1-MMP recycling and increased MT1-MMP-lysosome localization, which significantly affected the stability of MT1-MMP. Furthermore, our results indicated that VPS35/Retromer regulates the transcription of MT1-MMP by activating interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) inflammatory signaling pathway. Tissue microarray analysis indicated that VPS35/Retromer positively correlated with MT1-MMP levels and distant metastasis. Xenograft experiments showed that targeting VPS35/Retromer significantly inhibited melanoma lung metastasis, which is dependent on MT1-MMP. Our results implicate the importance of VPS35/Retromer in metastatic dissemination. Our study suggests that targeting the VPS35/Retromer-MT1-MMP axis will contribute to inhibiting the metastasis of melanoma.