Hyperactivated YAP1 Drives an Invasive EMT Subtype of Cervical Squamous Cell Carcinoma.

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Cervical cancer (CVC) is primarily HPV-driven, leading to successful screening strategies.
• Despite vaccination and screening, CVC mortality has plateaued, indicating a need to address detection-resistant subtypes.
• The World Health Organization aims to eliminate CVC as a public health problem.

Purpose of the Study:

• To investigate the molecular mechanisms driving a subset of invasive cervical cancer that evades current screening.
• To define the cellular and immune landscape of this HPV-independent CVC subtype.
• To identify potential new therapeutic targets for achieving CVC elimination.

Main Methods:

• Single-cell RNA sequencing
• High-resolution spatial transcriptomics
• Analysis of Hippo-YAP signaling pathway disruption

Main Results:

• Hyperactivation of YAP1 due to Hippo-YAP signaling disruption induces an HPV-independent invasive CVC subtype.
• This subtype lacks surface lesions, evading HPV and cytology-based detection.
• YAP1-driven tumors exhibit an EMT-high state and recruit immunosuppressive myeloid-derived suppressor cells, promoting invasion and progression.

Conclusions:

• Targeting disrupted Hippo signaling presents a novel strategy for detecting and treating CVC subsets missed by current screening.
• Addressing these detection-resistant CVC subtypes is crucial for global CVC elimination efforts.
• Understanding the molecular drivers and immune microenvironment of this subtype is key to developing effective interventions.