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Dev Cell. 2018 Mar 26;44(6):679-693.e5. doi: 10.1016/j.devcel.2018.02.024.

Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity.

Author information

1
Department of Cell Biology, Duke University, Durham, NC 27710, USA; Duke Cancer Institute, Duke University, Durham, NC 27710, USA; Division of Pulmonary Critical care, Department of Medicine, Duke University School of Medicine, 307 Research Dr., Nanaline Duke Building, Room 308, Durham, NC 27710, USA; Regeneration Next, Duke University, Durham, NC 27710, USA. Electronic address: purushothamarao.tata@duke.edu.
2
Department of Genetics, Systems Biology Institute, Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
4
Department of Cell Biology, Duke University, Durham, NC 27710, USA.
5
Department of Cell Biology, Duke University, Durham, NC 27710, USA; Medical Scientist Training Program, Duke University School of Medicine, Durham, NC 27710, USA.
6
Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
7
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
8
Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA; Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
9
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
10
Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Ludwig Center at Harvard, Boston, MA 02115, USA; Massachusetts General Hospital for Children, Pediatric Pulmonary Medicine, Boston, MA, USA.

Abstract

We show that the loss or gain of transcription factor programs that govern embryonic cell-fate specification is associated with a form of tumor plasticity characterized by the acquisition of alternative cell fates normally characteristic of adjacent organs. In human non-small cell lung cancers, downregulation of the lung lineage-specifying TF NKX2-1 is associated with tumors bearing features of various gut tissues. Loss of Nkx2-1 from murine alveolar, but not airway, epithelium results in conversion of lung cells to gastric-like cells. Superimposing oncogenic Kras activation enables further plasticity in both alveolar and airway epithelium, producing tumors that adopt midgut and hindgut fates. Conversely, coupling Nkx2-1 loss with foregut lineage-specifying SOX2 overexpression drives the formation of squamous cancers with features of esophageal differentiation. These findings demonstrate that elements of pathologic tumor plasticity mirror the normal developmental history of organs in that cancer cells acquire cell fates associated with developmentally related neighboring organs.

KEYWORDS:

Waddington landscape; developmental history; non-small cell lung cancers; transdifferentiation; tumor heterogeneity; tumor plasticity

PMID:
29587142
PMCID:
PMC5875457
DOI:
10.1016/j.devcel.2018.02.024
[Indexed for MEDLINE]
Free PMC Article

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