Molecular portraits of epithelial, mesenchymal, and hybrid states in lung adenocarcinoma and their relevance to survival

Mark J. Schliekelman, Ayumu Taguchi, Jun Zhu, Xudong Dai, Jaime Rodriguez, Muge Celiktas, Qing Zhang, Alice Chin, Chee Hong Wong, Hong Wang, Lisa McFerrin, Suhaida A. Selamat, Chenchen Yang, Evan M. Kroh, Kavita S. Garg, Carmen Behrens, Adi F. Gazdar, Ite A. Laird-Offringa, Muneesh Tewari, Ignacio I. WistubaJean P. Thiery, Samir M. Hanash

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Epithelial-to-mesenchymal transition (EMT) is a key process associated with tumor progression and metastasis. To define molecular features associated with EMT states, we undertook an integrative approach combining mRNA, miRNA, DNA methylation, and proteomic profiles of 38 cell populations representative of the genomic heterogeneity in lung adenocarcinoma. The resulting data were integrated with functional profiles consisting of cell invasiveness, adhesion, and motility. A subset of cell lines that were readily defined as epithelial or mesenchymal based on their morphology and E-cadherin and vimentin expression elicited distinctive molecular signatures. Other cell populations displayed intermediate/hybrid states of EMT, with mixed epithelial and mesenchymal characteristics. A dominant proteomic feature of aggressive hybrid cell lines was upregulation of cytoskeletal and actin-binding proteins, a signature shared with mesenchymal cell lines. Cytoskeletal reorganization preceded loss of E-cadherin in epithelial cells in which EMT was induced by TGFb. A set of transcripts corresponding to the mesenchymal protein signature enriched in cytoskeletal proteins was found to be predictive of survival in independent datasets of lung adenocarcinomas. Our findings point to an association between cytoskeletal and actinbinding proteins, a mesenchymal or hybrid EMT phenotype and invasive properties of lung adenocarcinomas. Cancer Res; 75(9); 1789-800.

Original languageEnglish (US)
Pages (from-to)1789-1800
Number of pages12
JournalCancer research
Volume75
Issue number9
DOIs
StatePublished - May 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Schliekelman, M. J., Taguchi, A., Zhu, J., Dai, X., Rodriguez, J., Celiktas, M., Zhang, Q., Chin, A., Wong, C. H., Wang, H., McFerrin, L., Selamat, S. A., Yang, C., Kroh, E. M., Garg, K. S., Behrens, C., Gazdar, A. F., Laird-Offringa, I. A., Tewari, M., ... Hanash, S. M. (2015). Molecular portraits of epithelial, mesenchymal, and hybrid states in lung adenocarcinoma and their relevance to survival. Cancer research, 75(9), 1789-1800. https://doi.org/10.1158/0008-5472.CAN-14-2535