SOX2 Is the Determining Oncogenic Switch in Promoting Lung Squamous Cell Carcinoma from Different Cells of Origin

Summary Lung squamous cell carcinoma (LSCC) is a devastating malignancy with no effective treatments, due to its complex genomic profile. Therefore, preclinical models mimicking its salient features are urgently needed. Here we describe mouse models bearing various combinations of genetic lesions predominantly found in human LSCC. We show that SOX2 but not FGFR1 overexpression in tracheobronchial basal cells combined with Cdkn2ab and Pten loss results in LSCC closely resembling the human counterpart. Interestingly, Sox2;Pten;Cdkn2ab mice develop LSCC with a more peripheral location when Club or Alveolar type 2 (AT2) cells are targeted. Our model highlights the essential role of SOX2 in commanding the squamous cell fate from different cells of origin and represents an invaluable tool for developing better intervention strategies.

• Publication year

  2016

• Venue

  Cancer Cell

• Publication date

  2016-10-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.ccell.2016.09.001PMID 27728803PMCID 5065004
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2015cited by this paper
• HTSeq—a Python framework to work with high-throughput sequencing data

  2014cited by this paper
• SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma

  2014cited by this paper
• Multiple cells-of-origin of mutant K-Ras–induced mouse lung adenocarcinoma

  2014influential reference
• Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression.

  2014cited by this paper
• Role of PTEN in basal cell derived lung carcinogenesis

  2014influential reference
• Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells

  2014influential reference
• Sox2 Cooperates with Lkb1 Loss in a Mouse Model of Squamous Cell Lung Cancer

  2014influential reference
• Comprehensive molecular profiling of lung adenocarcinoma

  2014cited by this paper
• Sox2 cooperates with inflammation-mediated Stat3 activation in the malignant transformation of foregut basal progenitor cells.

  2013cited by this paper
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  2013cited by this paper
• Cell of origin of lung cancer

  2013cited by this paper
• Gene-expression data integration to squamous cell lung cancer subtypes reveals drug sensitivity

  2013cited by this paper
• The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas.

  2013cited by this paper
• p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome

  2012cited by this paper
• Comprehensive genomic characterization of squamous cell lung cancers

  2012cited by this paper
• Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome

  2012cited by this paper
• Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients

  2012influential reference
• Morphologic and clinicopathologic features of lung squamous cell carcinomas expressing Sox2.

  2012cited by this paper
• Characterization of the nature of granulocytic myeloid‐derived suppressor cells in tumor‐bearing mice

  2012cited by this paper
• IκB Kinase Alpha and Cancer

  2012cited by this paper
• Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung.

  2011influential reference
• Cells of origin in cancer

  2011cited by this paper
• Myeloid cell diversification and complexity: an old concept with new turns in oncology

  2011influential reference
• Utility of 10 Immunohistochemical Markers Including Novel Markers (Desmocollin-3, Glypican 3, S100A2, S100A7, and Sox-2) for Differential Diagnosis of Squamous Cell Carcinoma from Adenocarcinoma of the Lung

  2011cited by this paper
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  2011influential reference
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  2011influential reference
• Global cancer statistics

  2011cited by this paper
• Evidence That SOX2 Overexpression Is Oncogenic in the Lung

  2010cited by this paper
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  2010cited by this paper
• Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer

  2010cited by this paper
• The biology of myeloid‐derived suppressor cells: The blessing and the curse of morphological and functional heterogeneity

  2010cited by this paper
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  2010cited by this paper
• Cell of origin of lung cancer

  2010cited by this paper
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  2010cited by this paper
• SOX2 Is an Oncogene Activated by Recurrent 3q26.3 Amplifications in Human Lung Squamous Cell Carcinomas

  2010cited by this paper
• The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium.

  2009influential reference
• Basal cells as stem cells of the mouse trachea and human airway epithelium

  2009cited by this paper
• Peripheral squamous cell carcinoma of lung: patterns of growth with particular focus on airspace filling.

  2009cited by this paper
• SOX2 Is an Amplified Lineage Survival Oncogene in Lung and Esophageal Squamous Cell Carcinomas

  2009cited by this paper
• The role of myeloid cells in the promotion of tumour angiogenesis

  2008cited by this paper
• Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources

  2008cited by this paper
• Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice1

  2008cited by this paper
• Rapid Adhesion to Collagen Isolates Murine Keratinocytes with Limited Long‐Term Repopulating Ability In Vivo Despite High Clonogenicity In Vitro

  2008cited by this paper
• Updates in non-small cell lung cancer.

  2008cited by this paper
• Lung cancer and lung stem cells: strange bedfellows?

  2007cited by this paper
• p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a

  2007cited by this paper
• p63 Is essential for the proliferative potential of stem cells in stratified epithelia.

  2007cited by this paper
• A global double‐fluorescent Cre reporter mouse

  2007cited by this paper
• Adjusting batch effects in microarray expression data using empirical Bayes methods.

  2007influential reference
• Capturing Heterogeneity in Gene Expression Studies by “ Surrogate Variable Analysis ”

  2007influential reference
• Efficient method to generate single‐copy transgenic mice by site‐specific integration in embryonic stem cells

  2006cited by this paper
• High-resolution genomic profiles of human lung cancer.

  2005cited by this paper
• From the Cover: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

  2005cited by this paper
• Identification of bronchioalveolar stem cells in normal lung and lung cancer.

  2005cited by this paper
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  2004cited by this paper
• A keratin K5Cre transgenic line appropriate for tissue‐specific or generalized cre‐mediated recombination

  2004influential reference
• Clinicopathologic features of peripheral squamous cell carcinoma of the lung.

  2004cited by this paper
• In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations.

  2004cited by this paper
• Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium.

  2004cited by this paper
• Clinicopathologic Characteristics of Peripheral Squamous Cell Carcinoma of the Lung

  2003cited by this paper
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  2003cited by this paper
• Pathology of lung cancer.

  2002influential reference
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• Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.

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• Transformation of alveolar type 2 cells to type 1 cells following exposure to NO2.

  1975cited by this paper
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