Molecular portraits of epithelial, mesenchymal, and hybrid States in lung adenocarcinoma and their relevance to survival.
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 TGFβ. 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 actin-binding proteins, a mesenchymal or hybrid EMT phenotype and invasive properties of lung adenocarcinomas.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Mark J
MJ
Schliekelman
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ayumu
A
Taguchi
Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York.
Jun
J
Zhu
Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York.
Xudong
X
Dai
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jaime
J
Rodriguez
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Muge
M
Celiktas
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Qing
Q
Zhang
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Alice
A
Chin
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Chee-Hong
CH
Wong
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hong
H
Wang
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Lisa
L
McFerrin
Department of Surgery, Biochemistry and Molecular Biology, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Suhaida A
SA
Selamat
Department of Surgery, Biochemistry and Molecular Biology, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Chenchen
C
Yang
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Evan M
EM
Kroh
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Kavita S
KS
Garg
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Carmen
C
Behrens
Hamon Center for Therapeutic Oncology Research, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
Adi F
AF
Gazdar
Department of Surgery, Biochemistry and Molecular Biology, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Ite A
IA
Laird-Offringa
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Muneesh
M
Tewari
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ignacio I
II
Wistuba
Institute of Molecular Cell Biology, Singapore. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Jean P
JP
Thiery
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. shanash@mdanderson.org.
Samir M
SM
Hanash
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D019175:DNA Methylation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics; D008840:Microfilament Proteins / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism
D015820:Cadherins; D035683:MicroRNAs; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; D014746:Vimentin