2025-10-29 08:30:02
Presenters: Singh AK1
Affiliations: 1Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of Health, Frederick, MD
Background: Pattern recognition receptors (PRRs), such as Toll-like receptor 4 (TLR4), detect pathogen-associated molecular patterns (PAMPs) and help maintain epithelial homeostasis. While their roles in infection and inflammation are well established, their function in skin carcinogenesis and host-microbiota interactions remains less understood. Analysis of The Cancer Genome Atlas (TCGA) revealed recurrent mutations in TLR4 in skin cancers, suggesting a potential tumor-suppressive role.
Methods: We used a mouse model with keratinocyte-specific IKKα deletion (Ikka.f/+K5. Cre), with or without TLR4 deficiency. Skin microbial composition was profiled, and 3D skin organoids were generated from murine keratinocytes. These organoids were exposed to tumor-associated bacterial communities to assess DNA damage (γH2AX), IL-1β expression, and lipid metabolism. Comparisons were made with Il4R-/- organoids. In vivo studies included antibiotic treatment and IL-4R signaling ablation.
Results: Ikka.f/+K5.Cre mice showed low tumor incidence, but concurrent TLR4 loss significantly increased squamous cell carcinoma (SCC) formation, with tumors showing loss of the wild-type Ikka allele. Microbiome profiling revealed increased bacterial burden and Firmicutes enrichment in IkkaΔKC/+; Tlr4-/- mice. Organoids exposed to these bacteria showed elevated DNA damage, IL-1β, and altered lipid metabolism responses absent in Il4R-/- organoids. Remarkably, IkkaΔKC/+; Il4R-/- mice were tumor-resistant. Antibiotics also suppressed tumorigenesis.
Conclusion: These findings identify a TLR4–microbiota–IL-4R axis promoting skin cancer in IKKα-deficient epithelium. The 3D organoid model is a valuable platform to study host-microbiota-immune interactions, and IL-4R signaling presents a promising therapeutic target for cancer prevention.
References:
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3 Peralta-Ramos JM, Calcagno ML, Salva MG, Fraccaroli L, De la Fuente AL, Rizzo MM, et al. Toll-like receptor 4 in cutaneous oncology: Dual roles in tumor promotion and suppression. Int J Oncol. 2019;54(6):1981-94. doi:10.3892/ijo.2019.4790.
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