Module map of stem cell genes guides creation of epithelial cancer stem cells.
Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and I kappa B alpha, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells.
Wong
David J
DJ
Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA.
Liu
Helen
H
Ridky
Todd W
TW
Cassarino
David
D
Segal
Eran
E
Chang
Howard Y
HY
D053687:Adult Stem Cells / Q000166:cytology / Q000502:physiology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D004848:Epithelium / Q000473:pathology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000502:physiology; D042822:Genomic Instability; D006801:Humans; D007124:Immunoenzyme Techniques; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C116115:MYCBP protein, human; D012333:RNA, Messenger; D014157:Transcription Factors