Abstract 5008: Crosstalk between epithelial-IKKα-deletion and symbiotic bacterial-fungal infection in skin carcinogenesis

Abstract

Abstract Bacteria and fungi, two major components of the microbiota, generally share niches and develop both antagonistic and symbiotic relationships, regulating the pathological impacts on the host. The epithelium is where the bacterial-fungal interaction occurs most abundantly, but the relationship between the epithelium, bacteria, and fungi on the pathogenesis of numerous diseases, particularly tumorigenesis, is poorly understood. IKKα is one of the crucial factors regulating the homeostasis of squamous epithelial tissues. Recently, our lab has established a mouse model that develops esophageal squamous cell carcinomas (SCCs) associated with IKKα reduction, inflammation and chronic fungal infection. Cladosporium cladosporioides was a major type of fungi identified in this mouse model. Because IKKα deletion in the keratinocytes causes impaired skin barrier, we hypothesized that loss of epithelial IKKα may control fungal colonization through regulating the barrier integrity and inflammation, resulting in tumor promotion. We thus generated IKKαf/f mice with inducible K15.Cre (IKKαf/f/K15.Cre) which is expressed in skin stem cells, which are important for the epidermal formation and hair follicle development. After ablating IKKα in K15 cells in the oral mucosa and skin, IKKαf/f/K15.Cre mice were orally inoculated with Cladosporium cladosporioides. Loss of epithelial IKKα showed disruption of skin barrier functions and bacterial colonization in the oral mucosa and skin, oral dysplasia and skin SCC development. Interestingly, oral infection with Cladosporium further promoted bacterial colonization as well as skin tumorigenesis in IKKαf/f/K15.Cre mice. This suggests that epithelial IKKα loss can provoke oral bacterial-fungal symbiosis which contributes to tumor promotion. To confirm this hypothesis, we treated Cladosporium-infected IKKαf/f/K15.Cre mice with amoxicillin, an antibiotic, through drinking water. Amoxicillin treatment remarkably reduced skin tumor incidence in fungal-infected IKKαf/f/K15.Cre mice, indicating that oral bacterial-fungal symbiosis indeed promotes skin SCC development driven by epithelial IKKα reduction. We also detected bacterial colonization in human skin SCC tissue array as well as IKKα mutation in 17% of human skin SCC patients from the Cancer Genome Atlas database, supporting that the crosstalk between epithelial IKKα and bacterial-fungal symbiosis in skin SCC promotion is relavent to human diseases. Taken together, our data demonstrate that loss of epithelial IKKα induces the bacterial-fungal symbiosis in oral mucosa, promoting skin tumors. This study will shed light on the importance of the epithelial-bacterial-fungal interaction in the pathogenesis, proposing epithelial IKKα as a novel regulator of the bacterial-fungal interaction. Citation Format: Na-Young Song, Jami Willette-Brown, Feng Zhu, Yinling Hu. Crosstalk between epithelial-IKKα-deletion and symbiotic bacterial-fungal infection in skin carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5008.