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 Liu
Juan Carlos Izpisua Belmonte
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;
11 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
12 University of the Chinese Academy of Sciences, Beijing 100049, China;
13 Insitute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China;
14 Beijing Institute for Brain Disorder, Beijing 100069, China
Funds: This work was supported by the National Key Research and Development Program of China (2015CB964800), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Natural Science Foundation of China (81625009, 81330008, 91749202, 81861168034), Program of Beijing Municipal Science and Technology Commission (Z151100003915072), Advanced Innovation Center for Human Brain Protection (117212, 3500-1192012), and Beijing Municipal Commission of Health and Family Planning PXM2018_026283_000002).
Received Date: 2019-04-01
Abstract
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: Sox2,
tumor,
CXCR2,
stratified epithelia
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