TY - JOUR
T1 - Mutations in foregut SOX2+ cells induce efficient proliferation via CXCR2 pathway
AU - Hishida, Tomoaki
AU - Vazquez-Ferrer, Eric
AU - Hishida-Nozaki, Yuriko
AU - Sancho-Martinez, Ignacio
AU - Takahashi, Yuta
AU - Hatanaka, Fumiyuki
AU - Wu, Jun
AU - Ocampo, Alejandro
AU - Reddy, Pradeep
AU - Wu, Min Zu
AU - Gerken, Laurie
AU - Shaw, Reuben J.
AU - Rodriguez Esteban, Concepcion
AU - Benner, Christopher
AU - Nakagawa, Hiroshi
AU - Guillen Garcia, Pedro
AU - Nuñez Delicado, Estrella
AU - Castells, Antoni
AU - Campistol, Josep M.
AU - Liu, Guang Hui
AU - Izpisua Belmonte, Juan Carlos
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
KW - CXCR2
KW - Sox2
KW - stratified epithelia
KW - tumor
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U2 - 10.1007/s13238-019-0630-3
DO - 10.1007/s13238-019-0630-3
M3 - Article
C2 - 31041783
AN - SCOPUS:85067614933
SN - 1674-800X
VL - 10
SP - 485
EP - 495
JO - Protein and Cell
JF - Protein and Cell
IS - 7
ER -