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Protein Cell. 2019 Jul;10(7):485-495. doi: 10.1007/s13238-019-0630-3. Epub 2019 Apr 30.

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

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
2
Universidad Catolica, San Antonio de Murcia, Campus de los Jeronimos 135, Guadalupe, 30107, Spain.
3
Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
4
Howard Hughes Medical Institute, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
5
Integrative Genomics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
6
Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
7
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, 19104, USA.
8
Department of Traumatology and Research Unit, Clinica CEMTRO, Av. Ventisquero de la Condesa, 42, Madrid, 28035, Spain.
9
Gastroenterology Department, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, 08036, Spain.
10
Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. ghliu@ibp.ac.cn.
11
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. ghliu@ibp.ac.cn.
12
University of the Chinese Academy of Sciences, Beijing, 100049, China. ghliu@ibp.ac.cn.
13
Insitute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. ghliu@ibp.ac.cn.
14
Beijing Institute for Brain Disorder, Beijing, 100069, China. ghliu@ibp.ac.cn.
15
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA. belmonte@salk.edu.

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.

KEYWORDS:

CXCR2; Sox2; stratified epithelia; tumor

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