Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting intertriginous areas and characterized by recurrent inflammatory lesions, including nodules and abscesses. It is associated with substantial morbidity and a marked impairment in quality of life. Although relatively common, with an estimated prevalence of 1–2% in the general population, there are still no curative treatments available. Limited understanding of the cellular and molecular mechanisms involved in disease initiation and progression continues to hamper the development of targeted therapeutic strategies. This thesis aimed to investigate two major complications of HS: the development of dermal fibrosis and the risk of non–UV-induced cutaneous squamous cell carcinoma (non–UV- induced cSCC), as well as to identify the mechanisms involved in the pathogenesis of follicular HS. By analyzing samples from patients with HS, we demonstrated that cadherin-11 (CDH11) is overexpressed in HS fibroblasts. Using primary fibroblasts derived from patients with HS and from healthy controls, we identified a key role for CDH11 in HS-associated dermal fibrosis. CDH11 alters the fibroblast transcriptomic signature and modulates signaling pathways related to fibrosis, extracellular matrix regulation, and inflammation. We identified a positive feedback loop between CDH11 and TGF-β, whereby CDH11 enhances both collagen production and TGF-β expression. In parallel, CDH11 promotes nuclear translocation of YAP and activates transcription of YAP target genes. Together, these findings highlight the role of CDH11 in HS-associated fibrosis and support the exploration of therapeutic strategies targeting CDH11. The occurrence of non–UV-induced cSCC in areas of chronic inflammation represents one of the most severe comorbidities of HS. We analyzed a retrospective cohort of 31 patients with non–UV-induced cSCC associated with HS or other etiologies. Targeted DNA sequencing of 523 cancer-related genes revealed a mutational landscape distinct from that of UV-induced cSCC. KMT2B emerged as the most frequently mutated gene in non–UV-induced cSCC. Functional assays demonstrated its role in cSCC cell migration in vitro, suggesting a likely contribution to the pathogenesis of non–UV-induced cSCC. To investigate the mechanisms underlying follicular HS, we performed single-cell RNA sequencing using the Chromium Single Cell Gene Expression Flex platform (10x Genomics) on lesional skin from patients with follicular HS and compared the results with samples from patients with typical early-stage HS. These findings contribute to a deeper understanding of the pathophysiological mechanisms specific to follicular HS. In conclusion, this work identifies a critical role for CDH11 in HS-associated dermal fibrosis and implicates KMT2B mutations in the pathogenesis of non–UV-induced cSCC. It also provides new insights into the pathophysiology of follicular HS.

Director: Dr. Benedicte Oulès 
Team: Aractingi-Fontaine (Biologie cutanée)