Direct reprogramming of oral epithelial progenitor cells to cancer stem cells at single cell resolution in vivo.

ABSTRACT

Tumor initiation represents the initial step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Most studies investigating cancer-driving mechanisms in solid tumors rely on analyses of established malignant lesions, and thus cannot directly capture processes underlying the reprogramming of normal progenitor cells into cancer cells. Here, using spatiotemporally controlled oncogene expression in a genetically engineered system we demonstrate that concomitant YAP activation and HPV E6-E7 -mediated inhibition of tumor suppressive pathways is sufficient to rapidly reprogram oral epithelial progenitor cells (OEPCs) into cancer stem cells (CSCs). Single cell analyses of these nascent CSCs revealed hallmark transcriptional programs driving tumor initiation. Importantly, these CSC-enriched expression signatures distinguish normal tissue from malignant head and neck tumors and are associated with poor patient survival. Elucidating mechanisms underlying OEPC to CSC reprogramming may offer new insights to halt the conversion of premalignant cells into invasive carcinoma. HIGHLIGHTS YAP and HPV E6-E7 reprogram oral epithelial progenitor cells into cancer stem cells. Single cell analyses reveal the transcriptional architecture of tumor initiation.CSC transcriptional programs distinguish normal tissue from carcinoma.CSC signatures are associated with poor head and neck cancer survival.