Extracellular Hsp90 Binds to and Aligns Collagen-1 to Enhance Breast Cancer Cell Invasiveness

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Extracellular heat shock protein 90 (eHsp90) is implicated in cancer invasion and metastasis.
• Previous research focused on eHsp90's role in 2D basement membrane invasion.
• eHsp90's function in 3D interstitial matrix (IM) invasion remains uncharacterized.

Purpose of the Study:

• To investigate the role of eHsp90 in cancer cell invasion through the 3D interstitial matrix (IM).
• To elucidate the mechanism by which eHsp90 interacts with collagen fibers in the IM.
• To determine the structural requirements of eHsp90 for IM invasion.

Main Methods:

• Collagen-1 binding assay to assess direct binding.
• Second harmonic generation (SHG) imaging to visualize collagen fiber alignment.
• Transwell invasion assays using breast cancer cells.
• Utilized Hsp90 conformation mutants and inhibitors.

Main Results:

• eHsp90 directly binds and aligns Collagen-1 fibers, a key component of the IM.
• eHsp90 significantly enhances breast cancer cell invasion through Collagen-1.
• The N-domain of Hsp90 mediates Collagen-1 binding, while its open conformation is critical for alignment and invasion.
• Hsp90's ATPase activity is not required for Collagen-1 binding or alignment.

Conclusions:

• This study reveals a novel mechanism for eHsp90 in promoting cancer cell invasion through the 3D interstitial matrix.
• eHsp90's interaction with and alignment of collagen fibers is crucial for invasion.
• Targeting eHsp90, particularly its open conformation, presents a potential therapeutic strategy to inhibit cancer metastasis.