SPINT1 regulates the aggressiveness of skin cutaneous melanoma and its crosstalk with tumor immune microenvironment

Abstract

statement (15-30 words) 29 A zebrafish model shows that Spint1a deficiency facilitates oncogenic transformation, 30 regulates the tumor/immune microenvironment crosstalk, accelerates the onset of 31 SKCM, and promotes metastatic invasion in cell autonomous and non-autonomous 32 manners.Abstract 35 Skin cutaneous melanoma (SKCM) is the deadliest form of skin cancer and 36 while incidence rates are declining for most cancers, they have been steadily rising for 37 SKCM worldwide. Serine protease inhibitor, kunitz-type, 1 (SPINT1) is a type II 38 transmembrane serine protease inhibitor that has been shown to be involved in the 39 development of several types of cancer. We report here a high prevalence of SPINT1 40 genetic alterations in SKCM patients and their association with altered tumor immune 41 microenvironment and poor patient survival. We used the unique advantages of the 42 zebrafish to model the impact of SPINT1 deficiency in early transformation, 43 progression and metastatic invasion of SKCM. Our results reveal that Spint1a 44 deficiency facilitates oncogenic transformation, regulates the tumor/immune 45 microenvironment crosstalk, accelerates the onset of SKCM and promotes metastatic 46 invasion. Notably, Spint1a deficiency is required at both cell autonomous and non-47 autonomous levels to enhance invasiveness of SKCM. These results suggest the 48 relevance of clinical intervention on this signaling pathway for precision SKCM 49 medicine. 50 51 52 53 54 55 Skin cutaneous melanoma (SKCM) originates from melanocytes, neural-crest 56 derived pigment-producing cells located in the epidermis, where their major function is 57 to protect keratinocytes from UV-induced DNA damage (Wellbrock and Arozarena, 58 2016). The malignant transformation of melanocytes generates this fatal form of skin 59 cancer with a complex multigenic etiology that becomes extremely difficult to treat 60 once it has metastasized. SKCM is the deadliest form of skin cancer (75% of deaths 61 related to skin cancer) and it is common in the Western world. Indeed, its global 62 incidence is 15-25 per 100,000 individuals (Schadendorf and Hauschild, 2014). While 63 incidence rates are declining for most cancers, they have been steadily rising for SKCM 64 worldwide (van Rooijen et al., 2017). Early detection is fundamental, since localized, 65 early stage SKCM can be surgically excised with little chance of recurrence with a 66 98.2% of patient survival rate after 5 year survival as reported by The Surveillance, 67 Epidemiology, and End Results (SEER) (NIH, 2019). Metastatic SKCM, however, is 68 still an often fatal disease with a 5-year survival rate of 15-20% (van Rooijen et al., 69 2017). 70 SKCM is one of the most recurrent types of cancer and its genetic heterogeneity 71 has led in recent years to join forces to determine SKCM causes and develop effective 72 therapies. Transformation of melanocytes into primary and then metastatic SKCM 73 requires a complex interplay of exogenous and endogenous events (Schadendorf et al., 74 2015). More ...

Bee pollen in zebrafish diet affects intestinal microbiota composition and skin cutaneous melanoma development

“…Following transplantation, fish were placed into recovery tanks and weekly evaluated for melanoma formation. SKCM cells used in our study show enhanced aggressiveness in adult zebrafish allotransplantation model and fish recipients transplanted can develop tumors with a significant high growth rate 51 . Thus, photographs from adult transplantation assays were obtained at 1, 2, 3 and 4 weeks post injection (wpi).…”

“…Zebrafish kita:Gal4 ; eGFP-HRAS-G12V , which express human oncogenic HRAS in melanocytes and spontaneously develop SKCM, were used as tumor donors (n = 2) for allotransplantation assays. All the next procedures were developed according to a previous study 51 . Briefly, primary melanoma tumors were excised from adult zebrafish once they had reached between 3 and 5 mm in diameter and right after the procedure individuals were euthanized with an overdose of tricaine (1.2 mg/mL).…”