Mutations in foregut SOX2+ cells induce efficient proliferation via CXCR2 pathway

Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as KrasG...

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Detalles Bibliográficos
Autores: Hishida, Tomoaki, Vazquez Ferrer, Eric, Hishida Nozaki, Yuriko, Sancho-Martinez, Ignacio, Takahashi, Yuta, Hatanaka, Fumiyuki, Wu, Jun, Ocampo, Alejandro, Reddy, Pradeep, Wu, Min-Zu, Gerken, Laurie, Shaw, Reuben J., Rodriguez Esteban, Concepción, Benner, Christopher, Nakagawa, Hiroshi, Guillen Garcia, Pedro, Nuñez Delicado, Estrella, Castells Garangou, Antoni, Campistol Plana, Josep M., Liu, Guang-Hui, Izpisúa Belmonte, Juan Carlos
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/146620
Acceso en línea:https://hdl.handle.net/2445/146620
Access Level:acceso abierto
Palabra clave:Tumors
Errors congènits del metabolisme
Inborn errors of metabolism
Descripción
Sumario:Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as KrasG12D and p53 deletion. GFP-based lineage-tracing experiments indicate that SOX2+ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 homozygous deletion is required for the acquisition of an invasive potential, and KrasG12D expression, but not p53 deletion, suffices for tumor formation. Global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics.

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