A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival.
K-ras mutations occur frequently in epithelial cancers. Using short hairpin RNAs to deplete K-Ras in lung and pancreatic cancer cell lines harboring K-ras mutations, two classes were identified-lines that do or do not require K-Ras to maintain viability. Comparing these two classes of cancer cells revealed a gene expression signature in K-Ras-dependent cells, associated with a well-differentiated epithelial phenotype, which was also seen in primary tumors. Several of these genes encode pharmacologically tractable proteins, such as Syk and Ron kinases and integrin beta6, depletion of which induces epithelial-mesenchymal transformation (EMT) and apoptosis specifically in K-Ras-dependent cells. These findings indicate that epithelial differentiation and tumor cell viability are associated, and that EMT regulators in "K-Ras-addicted" cancers represent candidate therapeutic targets.
Singh
Anurag
A
Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA 94306, USA.
Greninger
Patricia
P
Rhodes
Daniel
D
Koopman
Louise
L
Violette
Sheila
S
Bardeesy
Nabeel
N
Settleman
Jeff
J
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology