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Cancer Cell. 2014 May 12;25(5):590-604. doi: 10.1016/j.ccr.2014.03.033. Epub 2014 May 1.

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

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  • 1Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Belfer Institute For Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • 3Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China.
  • 5Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 8Department of Pathology and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 9Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • 10Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 11Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 12Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 13Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: phammerman@partners.org.
  • 14Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: carla.kim@childrens.harvard.edu.
  • 15Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Belfer Institute For Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: kwong1@partners.org.

Abstract

Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1(+)NGFR(+) fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR(+) cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24794706
[PubMed - indexed for MEDLINE]
PMCID:
PMC4112370
Free PMC Article

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