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Identifying the cellular origin of squamous skin tumors.

ABSTRACT: Squamous cell carcinoma (SCC) is the second most frequent skin cancer. The cellular origin of SCC remains controversial. Here, we used mouse genetics to determine the epidermal cell lineages at the origin of SCC. Using mice conditionally expressing a constitutively active KRas mutant (G12D) and an inducible CRE recombinase in different epidermal lineages, we activated Ras signaling in different cellular compartments of the skin epidermis and determined from which epidermal compartments Ras activation induces squamous tumor formation. Expression of mutant KRas in hair follicle bulge stem cells (SCs) and their immediate progeny (hair germ and outer root sheath), but not in their transient amplifying matrix cells, led to benign squamous skin tumor (papilloma). Expression of KRas(G12D) in interfollicular epidermis also led to papilloma formation, demonstrating that squamous tumor initiation is not restricted to the hair follicle lineages. Whereas no malignant tumor was observed after KRas(G12D) expression alone, expression of KRas(G12D) combined with the loss of p53 induced invasive SCC. Our studies demonstrate that different epidermal lineages including bulge SC are competent to initiate papilloma formation and that multiple genetic hits in the context of oncogenic KRas are required for the development of invasive SCC.

SUBMITTER: Lapouge G

PROVIDER: S-EPMC3088632 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Identifying the cellular origin of squamous skin tumors.

Lapouge Gaëlle G Youssef Khalil Kass KK Vokaer Benoit B Achouri Younes Y Michaux Cindy C Sotiropoulou Panagiota A PA Blanpain Cédric C

Proceedings of the National Academy of Sciences of the United States of America 20110418 18

Squamous cell carcinoma (SCC) is the second most frequent skin cancer. The cellular origin of SCC remains controversial. Here, we used mouse genetics to determine the epidermal cell lineages at the origin of SCC. Using mice conditionally expressing a constitutively active KRas mutant (G12D) and an inducible CRE recombinase in different epidermal lineages, we activated Ras signaling in different cellular compartments of the skin epidermis and determined from which epidermal compartments Ras activ ...[more]

PMID: 21502497

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Project description:The fascinating story of epidermal immunity begins in utero where the epidermal barrier derives from the ectoderm and evolves through carefully orchestrated biological processes, including periderm formation, keratinocyte differentiation, proliferation, cornification, and maturation, to generate a functional epidermis. Vernix caseosa derives from epidermal cells that mix with sebaceous lipids and coat the fetus during late gestation, likely to provide conditions for cornification. At birth, infants dramatically transition from aqueous conditions to a dry gaseous environment. The epidermal barrier begins to change within hours, exhibiting decreased hydration and low stratum corneum (SC) cohesion. The SC varied by gestational age (GA), transformed over the next 2-3 months, and differed considerably versus stable adult skin, as indicated by analysis of specific protein biomarkers. Regardless of gestational age, the increased infant SC proteins at 2-3 months after birth were involved in late differentiation, cornification, and filaggrin processing compared to adult skin. Additionally, the natural moisturizing factor (NMF), the product of filaggrin processing, was higher for infants than adults. This suggests that neonatal skin provides innate immunity and protection from environmental effects and promotes rapid, continued barrier development after birth. Functional genomic analysis showed abundant differences across biological processes for infant skin compared to adult skin. Gene expression for extracellular matrix, development, and fatty acid metabolism was higher for infant skin, while adult skin had increased expression of genes for the maintenance of epidermal homeostasis, antigen processing/presentation of immune function, and others. These findings provide descriptive information about infant epidermal immunity and its ability to support the newborn's survival and growth, despite an environment laden with microbes, high oxygen tension, and irritants.

Dataset Information

Identifying the cellular origin of squamous skin tumors.

Publications

Identifying the cellular origin of squamous skin tumors.

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