The aggressiveness of solid cancers, such as melanoma, relies on their metastatic potential. It has become evident that this key cause of mortality is largely conferred by the tumour-associated stromal cells, especially endothelial cells. In addition to their essential role in the formation of the tumour vasculature, endothelial cells significantly contribute to the establishment of the tumour microenvironment, thus enabling the dissemination of cancer cells. Melanoma tumour vascularization occurs through diverse biological processes. Vasculogenesis is the formation of de novo blood vessels from endothelial progenitor cells (EPCs), and recent research has shown the role of EPCs in melanoma tumour vascularization. A more detailed understanding of the complex role of EPCs and how they contribute to the abnormal vessel structures in tumours is of importance. Moreover, anti-angiogenic drugs have a limited effect on melanoma tumour vascularization, and the role of these drugs on EPCs remains to be clarified. Overall, targeting cancer vasculature remains a challenge, and the role of anti-angiogenic drugs and combination therapies in melanoma, a focus of this review, is an area of extensive exploration.

Vitiligo is an autoimmune skin disorder characterized by loss of melanocytes. Protease-mediated disruption of junctions between keratinocytes and/or keratinocyte intrinsic dysfunction may directly contribute to melanocyte loss. House dust mite (HDM), an environmental allergen with potent protease activity, contributes to respiratory and gut disease but also to atopic dermatitis and rosacea. To verify if HDM can contribute to melanocyte detachment in vitiligo and if so, by which mechanism(s). Using primary human keratinocytes, human skin biopsies from healthy and vitiligo patients, and 3D reconstructed human epidermis, we studied the effect of HDM on cutaneous immunity, tight and adherent junction expression and melanocyte detachment. HDM increased keratinocyte production of vitiligo-associated cytokines and chemokines and increased expression of TLR-4. This was associated with increased in situ MMP-9 activity, reduced cutaneous expression of adherent protein E-cadherin, increased soluble E-cadherin in culture supernatant and significantly increased number of supra-basal melanocytes in the skin. This effect was dose-dependent and driven by cysteine protease Der p1 and MMP-9. Selective MMP-9 inhibitor, Ab142180 restored E-cadherin expression and inhibited HDM-induced melanocyte detachment. Keratinocytes from vitiligo patients were more sensitive to HDM-induced changes than healthy keratinocytes. All results were confirmed in 3D model of healthy skin and in human skin biopsies. Our results highlight that environmental mite may act as an external source of PAMPs in vitiligo and topical MMP-9 inhibitors may be useful therapeutic targets. Whether HDM contributes to onset of flares in vitiligo remains to be tested in carefully controlled trials.

Regenerative capabilities of the endothelium rely on vessel-resident progenitors termed endothelial colony forming cells (ECFCs). This study aimed to investigate if these progenitors are impacted by conditions (i.e., obesity or atherosclerosis) characterized by increased serum levels of oxidized low-density lipoprotein (oxLDL), a known inducer of Endothelial-to-Mesenchymal Transition (EndMT). Our investigation focused on understanding the effects of EndMT on the self-renewal capabilities of progenitors and the associated molecular alterations. In the presence of oxLDL, ECFCs displayed classical features of EndMT, through reduced endothelial gene and protein expression, function as well as increased mesenchymal genes, contractility, and motility. Additionally, ECFCs displayed a dramatic loss in self-renewal capacity in the presence of oxLDL. RNA-sequencing analysis of ECFCs exposed to oxLDL validated gene expression changes suggesting EndMT and identified SOX9 as one of the highly differentially expressed genes. ATAC sequencing analysis identified SOX9 binding sites associated with regions of dynamic chromosome accessibility resulting from oxLDL exposure, further pointing to its importance. EndMT phenotype and gene expression changes induced by oxLDL in vitro or high fat diet (HFD) in vivo were reversed by the silencing of SOX9 in ECFCs or the endothelial-specific conditional knockout of Sox9 in murine models. Overall, our findings support that EndMT affects vessel-resident endothelial progenitor’s self-renewal. SOX9 activation is an early transcriptional event that drives the mesenchymal transition of endothelial progenitor cells. The identification of the molecular network driving EndMT in vessel-resident endothelial progenitors presents a new avenue in understanding and preventing a range of condition where this process is involved.

CLEC12B is a C-type lectin receptor involved in the inhibition of NKs-mediated cytotoxicity. We have previously shown that CLEC12B is predominantly expressed on melanocytes and inhibits melanin production and pigmentation as well as proliferation of melanoma. To date, the role of CLEC12B in skin immunity is unknown. Upon phosphorylation of its immunoreceptor tyrosine-based inhibitory motif, we demonstrate that CLEC12B increases the production of innate chemokines from human melanocytes through the activation of the signal transducer and activator of transcription 1/IFN regulatory factor 1-mediated IFNγ pathway, resulting in chemoattraction of immune cells. We have demonstrated CLEC12B to potentiate the effect of IFNγ in primed melanocytes. Furthermore, CLEC12B recognizes cutaneous (Staphylococcus aureus and E coli) but not gut (Listeria monocytogenes) bacteria and is capable of modulating their chemokine responses. Finally, we have shown that CLEC12B senses motifs present on human melanocytes and fibroblasts but not keratinocytes. Together, these results demonstrate that CLEC12B plays an important function in the human skin, bridging innate and adaptative immunity. This mechanism is of great interest because IFNγ and cellular recruitment are key initial steps involved in inflammation of many skin pathologies, making this receptor an interesting therapeutic target.