Novel Hybrid Phenotype Revealed in Small Cell Lung Cancer by a Transcription Factor Network Model That Can Explain Tumor Heterogeneity.

Udyavar AR, Wooten DJ, Hoeksema M, Bansal M, Califano A, Estrada L, Schnell S, Irish JM, Massion PP, Quaranta V
Cancer Res. 2017 77 (5): 1063-1074

PMID: 27932399 · PMCID: PMC5532541 · DOI:10.1158/0008-5472.CAN-16-1467

Small cell lung cancer (SCLC) is a devastating disease due to its propensity for early invasion and refractory relapse after initial treatment response. Although these aggressive traits have been associated with phenotypic heterogeneity, our understanding of this association remains incomplete. To fill this knowledge gap, we inferred a set of 33 transcription factors (TF) associated with gene signatures of the known neuroendocrine/epithelial (NE) and non-neuroendocrine/mesenchymal-like (ML) SCLC phenotypes. The topology of this SCLC TF network was derived from prior knowledge and was simulated using Boolean modeling. These simulations predicted that the network settles into attractors, or TF expression patterns, that correlate with NE or ML phenotypes, suggesting that TF network dynamics underlie the emergence of heterogeneous SCLC phenotypes. However, several cell lines and patient tumor specimens failed to correlate with either the NE or ML attractors. By flow cytometry, single cells within these cell lines simultaneously expressed surface markers of both NE and ML differentiation, confirming the existence of a "hybrid" phenotype. Upon exposure to standard-of-care cytotoxic drugs or epigenetic modifiers, NE and ML cell populations converged toward the hybrid state, suggesting possible escape from treatment. Our findings indicate that SCLC phenotypic heterogeneity can be specified dynamically by attractor states of a master regulatory TF network. Thus, SCLC heterogeneity may be best understood as states within an epigenetic landscape. Understanding phenotypic transitions within this landscape may provide insights to clinical applications. .

©2016 American Association for Cancer Research.

MeSH Terms (9)

Cell Differentiation Cell Line, Tumor Gene Expression Genetic Heterogeneity Humans Lung Neoplasms Phenotype Small Cell Lung Carcinoma Transcription Factors

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