Non-melanoma skin cancers (NMSCs), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are keratinocyte-derived malignancies that together comprise the most prevalent form of cancer in the US. SCCs arise from damaged epidermal basal and folliculo-infundibular keratinocytes (KC), most often evolving first into pre-cancerous actinic keratoses (AKs) that affect over 50 million Americans. Chronic ultraviolet B (UVB) light exposure has been implicated as the major environmental risk factor for development of AK and SCC, with both types of neoplasm harboring frequent mutations in the master cell cycle regulator p53 gene. We recently elucidated a critical, entirely unforeseen, role for Langerhans cells (LC) in cutaneous carcinogenesis, definitively demonstrating that LC exert major influences in both stimulating KC genotoxicity as well as facilitating tumor promotion. Under our hypothesis, LC act as detectors of physical and chemical epidermal perturbation and provide effector functions for the stimulation of KC genotoxicity (the hallmark transformation) and proliferation and dedifferentiation (the hallmarks of dysplasia and mutant clonal expansion). We have devised novel paradigms relating LC regulation of the epidermal stress response and IL-22-producing innate lymphoid (ILC) cells to UVB-induced carcinogenesis. For conditions of physiologic epidermal perturbation, under this construct, LC are poised to detect and respond to keratinocyte damage, eliciting from them precise, localized responses. However, when such epidermal perturbation leads to DNA-damaging exposure (e.g. chemical mutagen, ultraviolet radiation), resulting in KC acquisition of mutations that silence tumor-suppressor genes and/or constitutively activate oncogenes to support proliferation and resistance to apoptosis, a clonal expansion of the mutated KC ensues. In this way, tumor promotion usurps the normal physiologic response of LC, and chronic UVB exposure and stressed KCs stimulate LC to produce factors that drive KC transformation and mutant clonal expansion. We have shown in multiple models of cutaneous carcinogenesis that the net effect of these activities on the rates of clonal formation, clonal expansion and eventual tumor outgrowth are unequivocally dependent on the presence of LC, and we herein propose to identify the underlying mechanisms and begin to target them translationally. Toward this goal, we will pursue the following specific aims: (1) Elucidate the effector mechanisms underpinning LC facilitation of chronic UVB-induced cutaneous carcinogenesis; (2) Identify the key sensor components mediating LC facilitation of chronic UVB-induced cutaneous carcinogenesis; and (3) Investigate the potential to translationally inhibit LC-mediated mechanisms that facilitate cutaneous malignancy. To help accomplish these aims, we have developed an innovative strategy for the selective repopulation of LCs from precursor-rich fetal tissues that will enable us to fully elucidate the mechanisms by which LC facilitate chronic UVB-induced keratinocyte genotoxicity, epidermal proliferation and dedifferentiation, and mutant p53 KC clonal expansion.
Non-melanoma skin cancers, basal cell carcinomas and squamous cell carcinomas, together comprise the most prevalent form of cancer in the United States. Chronic sunlight exposure has been implicated as the major environmental risk factor for the development of skin cancer, and we recently elucidated a critical, entirely unforeseen, role for skin immune cells named Langerhans cells in causing chronic sunlight-induced skin cancer. We now propose to identify the mechanisms by which they do this, and then use this information to devise new strategies to prevent skin cancer.
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