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

Tomoaki Hishida,Estrella Núñez-Delicado ,Ignacio Sancho‐Martinez ,Eric Vazquez-Ferrer,Reuben J Shaw,Chris Benner ,Fumiyuki Hatanaka,Pedro Guillén García ,Guanghui Liu ,Concepción Rodrı́guez Esteban ,Pradeep Reddy,Josep M Campistol,Hiroshi Nakagawa,Alejandro Ocampo,Laurie Gerken,Jun Wu,Min-Zu Wu,Yuta Takahashi,Yuriko Hishida-Nozaki,Antoni Castells,Juan Carlos Izpisúa Belmonte

doi:10.1007/s13238-019-0630-3

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.

Highlights

Cancer arises from a progressive accumulation of genetic mutations in proto-oncogenes and tumor suppressor genes (Visvader and Lindeman, 2012; Blanpain and Simons, 2013)
Among Senescence-Associated Secretory Phenotype (SASP)-related factors, CXC chemokines that bind to CXC chemokine receptor 2 (CXCR2) have been shown to reinforce senescence, which results in growth arrest, further preventing tumor progression (Acosta et al, 2008)
Mcm2CreER/WT mice were bred with mice carrying a loxP-STOP-loxP (LSL)-oncogenic Kras (G12D) (KrasLSL-G12D/WT) and loxP-p53-loxP mice (p53Flox/Flox) (Marino et al, 2000; Jackson et al, 2001)

Summary

Introduction

Cancer arises from a progressive accumulation of genetic mutations in proto-oncogenes and tumor suppressor genes (Visvader and Lindeman, 2012; Blanpain and Simons, 2013). The oncogene Kras and the tumor suppressor gene p53 are frequently mutated in a wide range of human cancers (Serrano et al 1997; Kuilman et al, 2010) and are known to induce tumor initiation in a variety of mouse models (Jackson et al, 2001; Singh et al, 2010). Abnormal proliferative signals of oncogenic insults including oncogenic KRAS are known to activate a senescent phenotype in cells, presumably designed to prevent the growth of oncogene-transformed cells and to preserve the tumor in a non-aggressive state (Collado and Serrano, 2006). The effect of SASP on cell behavior is context-dependent

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Results

Conclusion