title: Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors.
abstract: Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 (-/-) mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 (-/-) mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression.
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM; IdiPAZ, Madrid 28029, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Villarejo
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM; IdiPAZ, Madrid 28029, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Molina-Ortiz
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM; IdiPAZ, Madrid 28029, Spain.
authors.forename: Yenny
authors.initials: Y
authors.lastname: Montenegro
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM; IdiPAZ, Madrid 28029, Spain, Fundación MD Anderson International Madrid, Madrid 28033, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM; IdiPAZ, Madrid 28029, Spain.
authors.forename: Saleta
authors.initials: S
authors.lastname: Morales
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM; IdiPAZ, Madrid 28029, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Santos
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Gridley
authors.affiliation: Cancer Biology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain and.
authors.forename: Mirna A
authors.initials: MA
authors.lastname: Pérez-Moreno
authors.affiliation: Department of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Héctor
authors.initials: H
authors.lastname: Peinado
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM; IdiPAZ, Madrid 28029, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Portillo
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM; IdiPAZ, Madrid 28029, Spain.
authors.forename: Carmela
authors.initials: C
authors.lastname: Calés
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM; IdiPAZ, Madrid 28029, Spain, acano@iib.uam.es.
authors.forename: Amparo
authors.initials: A
authors.lastname: Cano
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006410:Hematopoiesis; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D002273:Carcinogens; D012333:RNA, Messenger; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D015127:9,10-Dimethyl-1,2-benzanthracene