Biology subjects

Karakaya, T.

Publications and source records attributed to Karakaya, T..

3 recordsLinked to original sources

bioRxiv2026

p63 and PITX1 sustain a pre-invasive malignant keratinocyte population in squamous cell carcinoma precursors

BackgroundCutaneous squamous cell carcinoma (cSCC) is among the most common human cancers, yet the cellular identity and molecular programs of its preinvasive precursor, actinic keratosis (AK), remains poorly defined. MethodsWe applied CITE-seq to patient-matched AK, UV-exposed normal skin, and non-UV-exposed normal skin (n=5 patients, 12 biopsies) and performed spatial whole-transcriptome profiling in an independent cohort (n=4) to map pre-invasive keratinocyte states at single-cell resolution. ResultsWe identify AK-specific keratinocytes (ASK), a discrete population localized to the dysplastic basal epidermis and characterized by UV-associated mutational signatures (SBS7b), high mutational burden, and recurrent copy number alterations including 9p loss and 8q gain. ASK occupies a basal-like undifferentiated state sustained by a {Delta}Np63/PITX1 regulatory module that attenuates Notch/HES1-driven differentiation and activates glycolytic metabolism. Comparison with published cSCC data reveals that ASK share core tumor-propagating gene networks with tumor-specific keratinocytes (TSK), including IGFBP6, IGFBP2, and ITGA6, but lack invasion effectors MMP1, MMP10, and PTHLH. Functional experiments identify IGFBP6 as a pro-proliferative factor in AK-derived keratinocytes. The AK microenvironment shows expansion of inflammatory basal keratinocytes, barrier disruption, and early immunosuppressive T cell remodeling. ConclusionsThese findings define the molecular identity of a pre-invasive malignant keratinocyte population governed by p63/PITX1 and distinguish early oncogenic programs shared with invasive cSCC from later-acquired invasion effectors, identifying candidate targets for prevention or treatment of squamous cell carcinoma.

cancer biology↗

bioRxiv2025

NLRP1 inflammasome activation in skin equivalents revealsmechanistic insights into the roles of keratinocytes in psoriasis

Psoriasis is a major inflammatory skin disease for which a causal therapy is still not available. The pro-inflammatory cytokines interleukin(IL)-1{beta} and IL-36{gamma} are key drivers of the disease phenotype, but the mechanisms underlying their regulation in psoriasis remain poorly understood. Generation of IL-1{beta} activity is regulated by protein complexes, termed inflammasomes. We activated the NLRP1 inflammasome in human keratinocytes cultivated in three-dimensional skin equivalents. NLRP1 activation induced histological and molecular features that are highly reminiscent of psoriasis. Mechanistically, the phenotype was dependent on IL-1, which triggered a pro-inflammatory epidermal-dermal crosstalk. This included induction of expression of IL-36{gamma}, which, together with IL-1{beta}, was released from keratinocytes through NLRP1-induced gasdermin D pores. The in vivo relevance of these findings is reflected by the expression of the NLRP1 sensor and signs of inflammasome activation in lesional skin of psoriatic patients. Finally, we discovered endogenous cytoplasmic double stranded (ds) RNA, recently associated with cellular perturbations in psoriasis, as a novel activator of the NLRP1 inflammasome in human keratinocytes. Our results identify a novel endogenous double-stranded RNA-mediated NLRP1-IL-1-IL-36{gamma} signaling axis relevant in psoriasis and suggest targeting of this pathway as a promising treatment strategy.

immunology↗

bioRxiv2025

The skin commensal yeast Malassezia promotes tissue homeostasis via the aryl hydrocarbon receptor.

As an abundant fungal colonizer of human skin, Malassezia has long been associated with pathological skin conditions, yet its role in skin homeostasis remain poorly understood. Here, we demonstrate that Malassezia furfur plays an active role in maintaining epidermal integrity by producing tryptophan-derived metabolites that activate the aryl hydrocarbon receptor (AhR), a key regulator of keratinocyte differentiation and inflammation. Using a fungal mutant defective in indole production, we show that M. furfur-derived AhR activation is required to restore barrier function and control inflammation in diseased skin. AhR-deficient mice fail to benefit from M. furfur-mediated barrier protection, underscoring the importance of microbial-derived AhR agonists in skin physiology. These findings establish a previously unrecognized mutualistic role for Malassezia in epidermal homeostasis, challenging its perception as solely a pathogenic fungus and expanding our understanding of the skin microbiotas influence on barrier function and immune regulation. KEY FINDINGSO_LIMalassezia-derived indoles reprogram epidermal gene expression to enhance keratinocyte function. C_LIO_LIAhR activation by Malassezia restores skin barrier integrity and reduces inflammation. C_LIO_LIMalassezia Sul1-dependent tryptophan metabolism is essential for the production of AhR agonists. C_LIO_LIThe barrier protective effects of Malassezia are mediated specifically through keratinocyte intrinsic AhR signaling. C_LI

microbiology↗