A Fibroblast State Choreographs an Epithelial YAP-dependent Regenerative Program Essential to (Pre)malignancy via...

Area of Science:

• Cell Biology
• Oncology
• Tissue Engineering

Background:

• Chronic lung injury can lead to metaplasia, a precursor to squamous dysplasia and lung cancer.
• Disrupted tissue homeostasis plays a role in malignant initiation and progression.

Purpose of the Study:

• To identify mechanisms by which disrupted tissue homeostasis contributes to malignant initiation and progression.
• To investigate the role of fibroblasts and epithelial cells in injury-induced metaplasia and dysplasia.

Main Methods:

• Used in vivo and in vitro heterotypic recombinant models of human bronchial epithelial cells (hBECs) and fibroblasts.
• Analyzed TGF-β signaling, HSP47 upregulation, collagen accumulation, and mechanosignaling pathways.
• Investigated YAP-dependent activities in hBECs.

Main Results:

• Injury-associated TGF-β signaling induces a Stress/Tension-Instructive Fibroblast (STIF) state characterized by HSP47 upregulation and collagen accumulation.
• This STIF state increases tissue stiffness, activating YAP-dependent, pro-malignant activities in adjacent hBECs.
• STIFs are sufficient to reprogram normal hBECs to metaplasia and drive those with compromised tumor suppressor function to dysplasia, but this process is reversible.

Conclusions:

• The STIF state, characterized by increased force transmission, is sufficient to activate epithelial phenotypes resembling oncogene-mediated transformation and induce (pre)malignancy.
• STIF signaling alone, acting through fibroblasts, can induce metaplasia and program precancerous phenotypes in epithelial cells via mechanotransduction.
• Inhibition of STIF activity or mechanosignaling can prevent or reverse metaplasia and halt progression to dysplasia, identifying novel therapeutic targets.