Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs

Abstract

Non-melanoma skin cancer (NMSC) has risen dramatically as a result of chronic exposure to sunlight ultraviolet (UV) radiation, climatic changes and clinical conditions associated with immunosuppression. In spite of considerable progress, our understanding of the mechanisms that control NMSC development and their associated molecular and immunological landscapes is still limited. Here we demonstrated a critical role for galectin-7 (Gal-7), a β-galactoside-binding protein preferentially expressed in skin tissue, during NMSC development. Transgenic mice (Tg46) overexpressing Gal-7 in keratinocytes showed higher number of papillomas compared to WT mice or mice lacking Gal-7 (Lgals7−/−) when subjected to a skin carcinogenesis protocol, in which tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) and tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were sequentially administered. RNAseq analysis of Tg46 tumor lesions revealed a unique profile compatible with cells of the myelomonocytic lineage infiltrating these tumors, an effect that was substantiated by a higher number of CD11b+Gr1+ cells in tumor-draining lymph nodes. Heightened c-Met activation and Cxcl-1 expression in Tg46 lesions suggested a contribution of this pathway to the recruitment of these cells. Remarkably, Gal-7 bound to the surface of CD11b+Ly6ChiLy6Glo monocytic myeloid cells and enhanced their immunosuppressive activity, as evidenced by increased IL-10 and TGF-β1 secretion, and higher T-cell inhibitory activity. In vivo, carcinogen-treated Lgals7−/− animals adoptively transferred with Gal-7-conditioned monocytic myeloid cells developed higher number of papillomas, whereas depletion of these cells in Tg46-treated mice led to reduction in the number of tumors. Finally, human NMSC biopsies showed increased LGALS7 mRNA and Gal-7 protein expression and displayed transcriptional profiles associated with myeloid programs, accompanied by elevated CXCL1 expression and c-Met activation. Thus, Gal-7 emerges as a critical mediator of skin carcinogenesis and a potential therapeutic target in human NMSC.

Sorting nexin 3 exacerbates doxorubicin-induced cardiomyopathy via regulation of TFRC-dependent ferroptosis

“…Indeed, the mitochondria-targeted antioxidant MitoTEMPO substantially rescues Dox-induced cardiomyopathy, since sustaining mitochondrial oxidative damage is considered a major mechanism in ferroptosis-induced heart injury 12 . Accumulating evidence suggests that Dox-induced cardiomyocyte ferroptosis results from aberrant iron accumulation in cardiac mitochondria 7 , 13 . Since ferroptosis differs from other types of programmed cell death (PCD) which depending on their own routine cellular signaling pathways, suppression of ferroptosis might provide an alternative strategy that bypasses the apoptosis or necrosis pathway to improve the survival of Dox-induced cardiomyocyte death 14 , 15 .…”