Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation

// Anne-France Le Rolle 1 , Thang K. Chiu 3 , Zhaoshi Zeng 4 , Jinru Shia 5 , Martin R. Weiser 4 , Philip B. Paty 4 and Vi K. Chiu 1,2 ­ 1 Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA 2 Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA 3 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA 4 Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 5 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Correspondence to: Vi K. Chiu, email: // Keywords : KRAS, embryonic stem cell-like program, colorectal cancer, cancer plasticity, EMT Received : June 27, 2015 Accepted : December 30, 2015 Published : January 04, 2016 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 ( KRAS mut ) is the most prevalent oncogenic driver in colorectal cancer development, and KRAS mut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRAS mut 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 KRAS mut 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 KRAS mut 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 KRAS mut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRAS mut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRAS mut tumors and prevent colon cancer.