Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity.
Dev Cell, 2018/03/26;44(6):679-693.e5.
Tata PR[1], Chow RD[2], Saladi SV[3], Tata A[4], Konkimalla A[5], Bara A[4], Montoro D[6], Hariri LP[7], Shih AR[7], Mino-Kenudson M[7], Mou H[8], Kimura S[9], Ellisen LW[3], Rajagopal J[10]
Affiliations
PMID: 29587142DOI: 10.1016/j.devcel.2018.02.024
Impact factor: 13.417
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
MeSH terms
Adenocarcinoma, Mucinous; Animals; Carcinoma, Squamous Cell; Cell Differentiation; Cell Lineage; Cell Plasticity; Embryonic Development; Endoderm; Esophageal Neoplasms; Female; Gene Expression Regulation, Developmental; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prognosis; SOXB1 Transcription Factors; Signal Transduction; Stomach Neoplasms; Survival Rate; Thyroid Nuclear Factor 1
More resources
Full text:
Europe PubMed Central; PubMed Central
EndNote: Download