Hôpital de Beaumont

Tumors invade the surrounding tissues to progress, but the heterogeneity of cell types at the tumor-stroma interface and the complexity of their potential interactions hampered mechanistic insight required for efficient therapeutic targeting. Here, combining single-cell and spatial transcriptomics on human basal cell carcinomas, we define the cellular contributors of tumor progression. In the invasive niche, tumor cells exhibit a collective migration phenotype, characterized by the expression of cell-cell junction complexes. In physical proximity, we identify cancer-associated fibroblasts with extracellular matrix-remodeling features. Tumor cells strongly express the cytokine Activin A, and increased Activin A-induced gene signature is found in adjacent cancer-associated fibroblast subpopulations. Altogether, our data identify the cell populations and their transcriptional reprogramming contributing to the spatial organization of the basal cell carcinoma invasive niche. They also demonstrate the power of integrated spatial and single-cell multi-omics to decipher cancer-specific invasive properties and develop targeted therapies.

*Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne University Hospital Center, Lausanne, Switzerland; †Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, California Address correspondence and reprint requests to: François Kuonen, MD, PhD, Department of Dermatology and Venereology, Lausanne University Hospital Center, Av. de Beaumont 29, CH-1011 Lausanne, Switzerland, or e-mail: [email protected] The authors have indicated no significant interest with commercial supporters.

Background: Squamous cell carcinomas and basal cell carcinomas are both induced by chronic UV exposure. However, their predilection for specific areas of the face remains unexplained. Regional factors such as arterial blood flow may explain specific tumor localization. Objective: To determine whether in the fronto-temporal area of the face there is a preferential localization of non-melanoma skin cancer (NMSC) at sites of arterial blood vessels. Methods: Twenty-two patients with NMSC of the fronto-temporal area were selected for this study. The clinical tumor margins were demarked based on clinical examination. Arterial colocalization was determined using both sonography and histological analysis. Results: Echo-Doppler analysis revealed the colocalization of NMSC with an arterial branch in 59% of the patients. Histologically, colocalization between NMSC and artery was found in 68% of the patients. When combining echo-Doppler and histological results, colocalization of NMSC and arteries were found in 82% of the patients. Conclusion: In this study, we found an unexpectedly high colocalization of NMSC with arterial branches in the fronto-temporal area of the face. These results suggest that in addition to UV exposure, pulsatile arterial blood flow may represent an additional factor determining the precise facial localization of NMSC.

The diagnosis of nail psoriasis can be challenging when patients have no skin lesions. Biopsy of the nail matrix and bed is an invasive procedure and histological interpretation may be difficult. Further help in the diagnosis of nail psoriasis may come from reliable biomarkers. The role of extracellular microRNAs (miRNAs) has been implicated in the pathogenesis of several human diseases (e.g. breast cancer) and some authors proposed to use the serum and/or saliva miRNA levels as diagnostic, prognostic [...]

Microwaves are tested as a new treatment for human papilloma virus (HPV)-related cutaneous warts in a pilot phase I open label uncontrolled study. Microwaves have been applied to thermally ablate inoperable liver tumours, but have not previously been used on the skin [1]. In this issue of the European Journal of Dermatology, Bristow et al. present a study of 32 adult volunteers who were recruited with 54 refractory plantar warts, present for more than a year, with at least two failed treatments. [...]

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis.

Epidermolysis bullosa simplex (EBS) is an inherited skin fragility disorder caused by mutations in keratin intermediate filament proteins. While discoveries of these mutations have increased understanding of the role of keratins and other intermediate filaments in epithelial tissues, progress towards the development of therapy for these disorders is much slower. Cell culture model systems that display these structural defects are needed for analysis of the cellular consequences of the mutations and to enable possible therapeutic strategies to be developed. Our aim was to generate immortalized cell lines as such model systems for the study of EBS. We generated a series of stable cell lines expressing EBS-associated keratin mutations, by immortalizing keratinocytes from EBS-affected skin biopsies with either simian virus 40 (SV40) T antigen or human papillomavirus 16 (HPV16) E6/E7, and assessed their keratin expression (by immunofluorescence), proliferation rates and migratory behaviour (in outgrowth and scratch wound assays). Clonal immortalized keratinocyte cell lines KEB-1, KEB-2, KEB-3 (using SV40 T antigen) and KEB-4, KEB-7 and NEB-1 (using HPV16 E6/E7) were established. These include two lines from a single individual with Weber-Cockayne EBS (i.e. KEB-3 and KEB-4, mutation K14 V270M), and three cell lines from a second family, two from siblings carrying the same mutation (KEB-1, KEB-2 lines from Dowling-Meara EBS, mutation K5 E475G) and one from an unaffected relative (NEB-1). The sixth cell line (KEB-7), with a previously unreported severe mutation (K14 R125P), was the only one to show keratin aggregates in resting conditions. Despite variations in the immortalization procedure, there was no significant difference between cell lines in keratin expression, outgrowth capabilities or response to transient heat shock. However, cell migration, as measured by speed of scratch wound closure, was significantly faster in cells with severe EBS mutations. These cell lines provide useful culture systems in which to assess aspects of EBS-induced cell changes. The faster migration after scratch wounding of the EBS keratinocytes may be a consequence of the known upregulation of stress-activated kinase pathways in these cells.