Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity

Publication date: 26 March 2018
Source:Developmental Cell, Volume 44, Issue 6
Author(s): Purushothama Rao Tata, Ryan D. Chow, Srinivas Vinod Saladi, Aleksandra Tata, Arvind Konkimalla, Anne Bara, Daniel Montoro, Lida P. Hariri, Angela R. Shih, Mari Mino-Kenudson, Hongmei Mou, Shioko Kimura, Leif W. Ellisen, Jayaraj Rajagopal
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.

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Teaser

Many tumors are characterized by the loss or gain of transcription factors that govern embryonic cell-fate specification. Tata, Chow et al. show that elements of pathologic tumor plasticity mirror the developmental history of organs in that plastic cancer cells can acquire cell fates normally associated with developmentally related neighboring organs.


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