Publication date: Apr 17, 2019
Skin cutaneous melanoma (SKCM) is the deadliest form of skin cancer and while incidence rates are declining for most cancers, they have been steadily rising for SKCM worldwide. Serine protease inhibitor, kunitz-type, 1 (SPINT1) is a type II transmembrane serine protease inhibitor that has been shown to be involved in the development of several types of cancer. We report here a high prevalence of SPINT1 genetic alterations in SKCM patients and their association with altered tumor immune microenvironment and poor patient survival. We used the unique advantages of the zebrafish to model the impact of SPINT1 deficiency in early transformation, progression and metastatic invasion of SKCM. Our results reveal that Spint1a deficiency facilitates oncogenic transformation, regulates the tumor/immune microenvironment crosstalk, accelerates the onset of SKCM and promotes metastatic invasion. Notably, Spint1a deficiency is required at both cell autonomous and non-autonomous levels to enhance invasiveness of SKCM. These results suggest the relevance of clinical intervention on this signaling pathway for precision SKCM medicine.
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