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

Tomoaki Hishida, Eric Vazquez-Ferrer, Yuriko Hishida-Nozaki, Ignacio Sancho-Martinez, Yuta Takahashi, Fumiyuki Hatanaka, Jun Wu, Alejandro Ocampo, Pradeep Reddy, Min Zu Wu, Laurie Gerken, Reuben J. Shaw, Concepcion Rodriguez Esteban, Christopher Benner, Hiroshi Nakagawa, Pedro Guillen Garcia, Estrella Nuñez Delicado, Antoni Castells, Josep M. Campistol, Guang Hui LiuJuan Carlos Izpisua Belmonte

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)485-495
Number of pages11
JournalProtein and Cell
Volume10
Issue number7
DOIs
StatePublished - Jul 1 2019
Externally publishedYes

Keywords

  • CXCR2
  • Sox2
  • stratified epithelia
  • tumor

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Drug Discovery
  • Cell Biology

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  • Cite this

    Hishida, T., Vazquez-Ferrer, E., Hishida-Nozaki, Y., Sancho-Martinez, I., Takahashi, Y., Hatanaka, F., Wu, J., Ocampo, A., Reddy, P., Wu, M. Z., Gerken, L., Shaw, R. J., Rodriguez Esteban, C., Benner, C., Nakagawa, H., Guillen Garcia, P., Nuñez Delicado, E., Castells, A., Campistol, J. M., ... Izpisua Belmonte, J. C. (2019). Mutations in foregut SOX2+ cells induce efficient proliferation via CXCR2 pathway. Protein and Cell, 10(7), 485-495. https://doi.org/10.1007/s13238-019-0630-3