RESUMO
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.
Assuntos
Carcinoma de Células Escamosas/fisiopatologia , Linhagem da Célula/fisiologia , Células Epidérmicas , Neoplasias Cutâneas/fisiopatologia , Animais , Bromodesoxiuridina , Carcinoma de Células Escamosas/genética , Primers do DNA/genética , Citometria de Fluxo , Folículo Piloso/citologia , Integrases/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/genética , Células-Tronco/metabolismoRESUMO
For most types of cancers, the cell at the origin of tumour initiation is still unknown. Here, we used mouse genetics to identify cells at the origin of basal cell carcinoma (BCC), which is one of the most frequently occurring types of cancer in humans, and can result from the activation of the Hedgehog signalling pathway. Using mice conditionally expressing constitutively active Smoothened mutant (SmoM2), we activated Hedgehog signalling in different cellular compartments of the skin epidermis and determined in which compartments Hedgehog activation induces BCC formation. Activation of SmoM2 in hair follicle bulge stem cells and their transient amplifying progenies did not induce cancer formation, demonstrating that BCC does not originate from bulge stem cells, as previously thought. Using clonal analysis, we found that BCC arises from long-term resident progenitor cells of the interfollicular epidermis and the upper infundibulum. Our studies uncover the cells at the origin of BCC in mice and demonstrate that expression of differentiation markers in tumour cells is not necessarily predictive of the cancer initiating cells.
Assuntos
Carcinoma Basocelular/patologia , Linhagem da Célula , Epiderme/patologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Caderinas/metabolismo , Carcinoma Basocelular/metabolismo , Contagem de Células , Diferenciação Celular , Células Clonais/metabolismo , Células Clonais/patologia , Orelha Externa/patologia , Epiderme/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Genes Reporter/genética , Folículo Piloso/metabolismo , Folículo Piloso/patologia , Proteínas Hedgehog/genética , Integrases/genética , Integrina beta4/metabolismo , Queratina-10/metabolismo , Queratina-14/genética , Queratina-15/genética , Queratina-15/metabolismo , Queratina-19/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores Patched , Proteínas/genética , Proteínas/metabolismo , RNA não Traduzido , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Pele/metabolismo , Pele/patologia , Receptor Smoothened , Cauda/patologiaRESUMO
Merkel cells (MCs) are located in the touch-sensitive area of the epidermis and mediate mechanotransduction in the skin. Whether MCs originate from embryonic epidermal or neural crest progenitors has been a matter of intense controversy since their discovery >130 yr ago. In addition, how MCs are maintained during adulthood is currently unknown. In this study, using lineage-tracing experiments, we show that MCs arise through the differentiation of epidermal progenitors during embryonic development. In adults, MCs undergo slow turnover and are replaced by cells originating from epidermal stem cells, not through the proliferation of differentiated MCs. Conditional deletion of the Atoh1/Math1 transcription factor in epidermal progenitors results in the absence of MCs in all body locations, including the whisker region. Our study demonstrates that MCs arise from the epidermis by an Atoh1-dependent mechanism and opens new avenues for study of MC functions in sensory perception, neuroendocrine signaling, and MC carcinoma.