Abstract
CYLD cutaneous syndrome (CCS) is a progressive genetic condition lacking medical therapies. CCS skin tumours are driven primarily by loss of heterozygosity of germline CYLD pathogenic variants (PVs) associated with deregulated NF-κB signalling. We demonstrate evidence of non- canonical NF-κB signalling in CCS tumours, with increased p100 to p52 processing and RelB protein. To distinguish tumour keratinocytes from immune cell contributions to NF-κB signalling in the tumour microenvironment, we flow sorted CCS tumour cells into CD45- and CD45+ fractions. Transcriptomic profiling revealed CD45- CCS cells were enriched for CCS tumour keratinocytes, and expressed CCS signature hair keratins. Differentially expressed genes in CD45- CCS cells compared to CD45- control cells were analysed for the presence of p52/RelB heterodimer binding motifs in their regulatory regions. Of these, EDAR was the most differentially expressed. To validate the CCS CD45-- transcriptomic profile in CCS tumour initiating cells, CD200+CD45- CCS tumour cells were subject to proteomic profiling. EDAR was the predominant NF-κB pathway cell surface receptor detected, alongside increased TRAF2, TRAF6 and IKKα. To interrogate CCS non-canonical NF-κB signalling, we cultured genotyped, patient-derived, CCS keratinocytes, revealing a truncated CYLD (trCYLD) corresponding to the predicted size of the patient’s truncating pathogenic variant. Tumour spheroid cultures generated from these cells expressed EDAR, trCYLD and increased p100. Exposure to a novel, highly selective, IKKα inhibitor SU1644 in patient derived CCS tumour spheroid cultures reduced viability and was associated with reduced levels of pathogenic trCYLD and p100 to p52 processing. These data provide the pre-clinical rationale for the assessment of IKKα inhibitors as a treatment for CCS.
Original language | English |
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Pages (from-to) | S268 |
Number of pages | 1 |
Journal | Journal of Investigative Dermatology |
Volume | 144 |
Issue number | 12 |
Early online date | 20 Nov 2024 |
DOIs | |
Publication status | Published - Dec 2024 |
Event | European Society for Dermatological Research (ESDR) 2024 - Lisbon, Portugal Duration: 4 Sept 2024 → 7 Sept 2024 |