Project ID CM-HD2023_32

ThemeCM-HD

Co Supervisor 1A FoDOCS, CHMIWebsite

Co Supervisor 1B FoDOCS, CHMIWebsite

Promotion of oral carcinogenesis by Candida albicans

Head and neck cancers (HNC) are oral squamous cell carcinomas (OSCC) that develop in fields premalignant mucosa, histologically diagnosed as oral epithelial dysplasia (OED). Chronic infection is associated with OED and OSCC but the mechanisms driving these associations are unclear.

Candida albicans (C.alb) is a commensal fungus causing oral Chronic Hyperplastic Candidiasis, which is associated with malignancy. C.alb enhance genes/proteins associated with tumour-promoting signalling pathways, metabolic changes, and metastasis in vitro and promotes oncogenesis in vivo. Cancer-associated processes/markers appear to be driven by candidalysin, a peptide toxin secreted by C.alb.

Aim: To determine the role of C.alb infection and candidalysin in driving oral carcinogenesis
1. Year 1: Monolayer/organotypic primary oral epithelial models will be assessed for induction of oncogenic markers after exposure to C.alb and candidalysin by qRT-PCR, immunohistochemistry, and immunoblot. Markers of cell growth/proliferation, differentiation, epithelial-mesenchymal transition, DNA repair, cell and nuclear signalling, and cell death will be assessed.
2. Year 2: Role of EGFR in activating candidalysin-induced oncogenic markers will be determined by using cell lines, EGFR knockdown (siRNAs), or inhibiting/blocking EGFR signalling. Epithelial/fungal transcriptomes will be analysed via RNASeq to identify additional potential oncogenic pathways against The Cancer Genome Atlas. Changes in the metabolome will be determined using NMR.
3. Year 3: Validate findings in a murine model of oral cancer using candidalysin-producing/deficient C.alb in the presence/absence of EGFR inhibitors, and in archival patient oral biopsies. Immunohistochemistry, RT-PCR, and RNAScope/Nanostring will confirm the presence of candidalysin and the above-identified markers to provide validation in OED and HNC.

One representative publication from each co-supervisor:

• Vadovics M, Ho J, Igaz N, Alföldi R, Rakk D, Veres É, Szücs B, Horváth M, Tóth R, Szücs A, Csibi A, Horváth P, Tiszlavicz L, Vágvölgyi C, Nosanchuk JD, Szekeres A, Kiricsi M, Henley-Smith R, Moyes DL, Thavaraj S, Brown R, Puskás LG, Naglik JR, Gácser A (2022). Candida albicans enhances the progression of oral squamous cell carcinoma in vitro and in vivo. mBio 13 (1), e0314421.

• Moyes DL, Wilson D, Richardson JP, Tang SX, Wernecke J, Höfs S, Gratacap RL, Mogavero S, Robbins J, Runglall M, Murciano C, Blagojevic M, Thavaraj S, Förster TM, Hebecker B, Kasper L, Vizcay G, Iancu SI, Kichik N, Häder A, Kurzai O, Cota E, Bader O, Wheeler RT, Gutsmann T, Hube B and Naglik JR (2016). Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature 532, 64-68