Our findings indicate that once a minimal complement of pathway alterations is achieved – loss of TP53 and CDKN2A function and YAP activation – OEPCs are rapidly reprogrammed into CSCs endowed with hallmarks of invasive carcinoma, including cell cycle progression, hypoxia, squamous differentiation defects, interferon responses, and a pEMT cell identity. The gene discussed is YAP1; the disease is invasive carcinoma.