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

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.