title: Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation.
abstract: Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA.
authors.forename: Anne-France
authors.initials: AF
authors.lastname: Le Rolle
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Thang K
authors.initials: TK
authors.lastname: Chiu
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA.|Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA.
authors.forename: Vi K
authors.initials: VK
authors.lastname: Chiu
mesh_terms: D016475:3T3 Cells; D000236:Adenoma / Q000473:pathology*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000473:pathology*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: C116884:LGR5 protein, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D043562:Receptors, G-Protein-Coupled; D016283:Proto-Oncogene Proteins p21(ras)
keywords: EMT; KRAS; cancer plasticity; colorectal cancer; embryonic stem cell-like program