Shear Stress Promotes Metastasis of Triple-negative Breast Cancer Cells Through Calcium Channel-ROS-FOS Axis

Area of Science:

• Oncology
• Biophysics
• Molecular Biology

Background:

• Circulating tumor cells (CTCs) face shear stress (SS) during metastasis, which can paradoxically enhance malignancy.
• Reactive oxygen species (ROS) play critical roles in cancer progression and stress responses.

Purpose of the Study:

• To investigate the interplay between SS, ROS, and metastasis using a microfluidic system.
• To identify molecular mechanisms linking SS-induced ROS production to enhanced metastatic potential in triple-negative breast cancer (TNBC).

Main Methods:

• Engineered a circulation-mimicking microfluidic system to apply pulsatile SS.
• Treated TNBC cells with SS and measured ROS levels, metastatic abilities, gene expression (RNA-sequencing), and protein localization.
• Utilized orthotopic tumor models and calcium channel blockers (Mibefradil, Nifedipine) for in vivo validation.

Main Results:

• A 3-hour SS treatment rapidly elevated ROS levels and boosted metastatic abilities in TNBC cells.
• SS stimulation induced ROS-dependent upregulation and nuclear localization of AP-1 transcription factors (FOS, ATF3, FOSB).
• FOS demonstrated the strongest metastasis-promoting potential, triggering lung metastasis and correlating with poor clinical outcomes. Calcium channels were identified as mechano-sensors initiating the SS-ROS cascade.

Conclusions:

• The SS-calcium channel-ROS-FOS axis promotes breast cancer metastasis.
• Targeting this axis, particularly FOS activation or calcium channel activity, may offer novel therapeutic strategies against metastatic breast cancer.