YAP-driven malignant reprogramming of oral epithelial stem cells at single cell resolution.

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Tumor initiation is the critical first step in cancer development.
• Understanding the in vivo reprogramming of normal cells to tumor-initiating cells is challenging.
• Oral epithelial progenitor cells are susceptible to malignant transformation.

Purpose of the Study:

• To elucidate the molecular mechanisms of oral epithelial progenitor cell reprogramming into tumor-initiating cells.
• To investigate the role of oncogene activation and tumor suppressor inhibition in cancer initiation.
• To analyze these processes at single-cell resolution using multiomics.

Main Methods:

• Spatiotemporally controlled oncogene activation and tumor suppressor inhibition.
• Single-cell resolution multiomics analysis.
• In vivo modeling of oral tumorigenesis.

Main Results:

• Tumor-initiating cells exhibit a stem-like state with aberrant proliferation, hypoxia, squamous differentiation, and partial epithelial-to-mesenchymal transition.
• YAP-mediated programs activate oncogenic networks, mTOR signaling, and myeloid cell recruitment for tumor infiltration.
• Identified conserved transcriptional programs in human head and neck cancers linked to poor survival.

Conclusions:

• Uncovered the single-cell resolution processes of cancer initiation in oral epithelium.
• Highlighted YAP signaling as a key driver in tumor-initiating cell reprogramming.
• Identified conserved programs and potential therapeutic targets for early cancer detection and prevention.