Project ID CM-HD2023_18


Co Supervisor 1A Faculty of Life Sciences & MedicineWebsite

Co Supervisor 1B BMBS/GRIDAWebsite

Investigating the role of STAT3 and the chronic inflammatory microenvironment as a driver of cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa

Cutaneous squamous cell carcinomas (cSCC) complicating the inherited blistering skin disease, recessive dystrophic epidermolysis bullosa (RDEB), is a strikingly aggressive cancer, with 87% of patients dying of metastatic disease by the age of 45 years. RDEB-cSCC arise at sites of scarring, chronic inflammation and aberrant wound healing associated with RDEB. Chronic activation of STAT3 is linked to inflammation and malignant transformation. We have demonstrated that inhibition of STAT3 activation using a JAK kinase inhibitor leads to tumour regression in xenograft mouse and spheroid models (figure 1) of RDEB-cSCC. This project will examine the hypothesis that the chronic inflammatory microenvironment associated with RDEB mediates aberrant STAT3 signalling driving the development and progression of RDEB-cSCC.

1. Define the spatial and temporal expression pattern of the STAT3/pY-STAT3/pS-STAT3 in RDEB-cSCC and sporadic cSCC cell lines. (Year 1)
2. Identification of potential biomarkers and therapeutic targets using digital spatial profiling of STAT3 signalling pathways (RNA and protein) in lesional and non-lesional skin from RDEB-cSCC and sporadic cSCC. (Years 1-2).
3. Functional validation via pharmacological and genetic perturbation of potential targets identified (from objective 2) in RDEB SCC cell lines and spheroid models (Years 2-3.5)

One representative publication from each co-supervisor:

• Jacków J, Rami A, Hayashi R, Hansen C, Guo Z, DeLorenzo D, Pappalardo A, Alvarez Cespedes D, Kim AL, Perez-Lorenzo R, Owens DM, Christiano AM. Targeting the Jak/Signal Transducer and Activator of Transcription 3 Pathway with Ruxolitinib in a Mouse Model of Recessive Dystrophic Epidermolysis Bullosa-Squamous Cell Carcinoma. J Invest Dermatol. 2021 Apr;141(4):942-946. doi: 10.1016/j.jid.2020.08.022. PMID: 33069729.

• Butler RM, McKenzie RC, Jones CL, Flanagan CE, Woollard WJ, Demontis M, Ferreira S, Tosi I, John S, Whittaker SJ, Mitchell TJ. Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance. J Invest Dermatol. 2019 Mar 22. pii: S0022-202X(19)31340-5. doi: 10.1016/j.jid.2019.03.1130. PubMed PMID: 30910759