Contribution of bioactive lipid mediators to inflammation and epithelial cancer development

Epithelial cells (ECs) line body-surface tissues, such as the skin, and are continuously exposed to potentially noxious and carcinogenic environmental substances. EC-derived cancers make up the majority of all cancers with non-melanoma skin cancer being the most common. The treatment of advanced cutaneous squamous cell carcinoma (cSCC) is an area of important unmet clinical need.

We have previously demonstrated that the skin has an active immune-surveillance system with tissue-resident immune cells providing strong host-protective responses against skin carcinogenesis.

This potent tumour immune-surveillance system is primarily driven by ECs, which upon tissue-damage produce an array of immune-modulating cytokines and bioactive lipid mediators that can initiate controlled inflammation, followed by efficient resolution.

Whilst the role of cytokines in regulating skin immunity have been extensively studied, very little is known of how bioactive lipid mediators contribute to skin homeostasis, inflammation and cancer.

We have found that bioactive lipid mediators in the skin are significantly altered in inflammation and cSCC and hypothesise that an in-balance between key inflammatory and resolving lipid mediators facilitate EC-tumour growth.

An understanding of how these bioactive lipid mediators influence dysregulated or cancerous ECs and the tissue immune-microenvironment is needed and could facilitate development of novel anticancer therapies.

The core aim of this proposal is to identify and characterise mechanism(s) whereby bioactive lipid mediators regulate epithelial carcinogenesis.

We will study cSCC carcinogenesis and focus on the lipoxygenase (LOX)-pathway and how its metabolite lipids modify the tissue-microenvironment during DNA-damage, chronic inflammation and cancer development.

We intend to: i) analyse which bioactive lipid mediators, and metabolising enzymes, regulate skin inflammation and tumour growth; ii) identify which signalling receptors are accountable for lipid responses; iii) assess the contribution of eosinophils to the bioactive lipidome and skin carcinogenesis and iv) explore effects of using LOX-inhibitors and/or treatment with specific lipid mediators to prevent skin inflammation and tumour promotion.

We will study clinical samples as well as mouse models of inflammation and cancer using a combination of genetic and pharmacologic manipulation of LOX-enzymes and their specific lipid products and/or signalling receptors. Skin responses will be explored using mass-spectrometry, qRT-PCR, multiplex-immunohistochemistry and flow cytometry.

The results will unravel the role of LOX-driven bioactive lipid mediators in epithelial cancer immune-surveillance.

This will add to our knowledge of cancer immunology, define the importance of specific bioactive lipid mediators and eosinophils in skin biology and may point to novel therapeutic strategies for both chronic inflammatory disorders and epithelial malignancies.