RHAMM regulates MMTV-PyMT-induced lung metastasis by connecting STING-dependent DNA damage sensing to...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis Research

Background:

• RHAMM (Receptor for Hyaluronic acid mediated motility) is upregulated in breast tumors and linked to metastasis risk.
• RHAMM influences cell cycle and migration, but its role in breast cancer metastasis is not fully understood.

Purpose of the Study:

• To investigate the role of RHAMM in breast cancer metastasis using a loss-of-function mouse model.
• To elucidate the molecular mechanisms by which RHAMM affects metastatic potential and tumor cell survival.

Main Methods:

• Utilized MMTV-PyMT mouse model crossed with Rhamm knockout mice for loss-of-function studies.
• Performed in vitro analyses, RNA-seq, and CRISPR/Cas9 gene editing to study RHAMM's function.
• Investigated somatic mutations and transcriptome changes associated with Rhamm-loss.

Main Results:

• Rhamm-loss increased lung metastasis without affecting primary tumor growth.
• RHAMM deficiency enhanced tumor cell survival against ROS-mediated DNA damage.
• Loss of RHAMM blunted STING-IFN signaling, reducing apoptosis induced by STING agonists, particularly in the lung microenvironment.

Conclusions:

• RHAMM loss confers a survival advantage to metastatic breast cancer cells in the lung via blunted STING-IFN signaling.
• RHAMM expression may serve as a predictive marker for sensitivity to interferon-based therapies.