Study reveals how extracellular matrix stiffness regulates breast cancer metastasis

A study by researchers at the University of California San Diego could make it easier to treat breast cancer by uncovering a new way the body helps prevent its spread. The scientists discovered a new role for an inflammatory protein called TYK2 in mechanotransduction, the process by which cells sense and respond to their physical environment. Understanding mechanotransduction can provide insights into how cancer spreads and provide new avenues for treatment.

Additionally, because drugs that inhibit TYK2 are being explored as treatments for autoimmune diseases, the study highlights the need to consider these drugs' impact on breast cancer progression.

The researchers found:

• TYK2 acts as a critical breast cancer metastasis suppressor in response to stiffness in the extracellular matrix, the material surrounding and connecting cells.
• At low stiffness, TYK2 is found on the cell membrane, where it stops cancer cells from invading. At high stiffness, TYK2 is inactivated and found throughout the cell, allowing cancer cells to invade.
• In mice, inhibiting TYK2 with drugs promoted breast cancer invasion and metastasis.

Understanding how TYK2 functions as a metastasis suppressor could pave the way for new treatments for breast cancer. The study's findings also suggest that patients with certain types of noninvasive breast cancer could be at higher risk of developing invasive breast cancer when receiving TYK2 inhibitors. This highlights the need for enhanced breast cancer screening in patients treated with TYK2 inhibitors.

This study reveals how extracellular matrix stiffness regulates breast cancer metastasis through TYK2 and provides new insights into how physical cues in the tumor microenvironment control cancer progression."

Zhimin Hu, PhD, lead author of this study and project scientist at UC San Diego Moores Cancer Center

"Our findings have significant implications for the clinical use of TYK2 inhibitors and underscore the importance of considering the mechanical microenvironment in cancer therapy," said Jing Yang, PhD, corresponding author and professor of pharmacology at UC San Diego School of Medicine. Yang is also a member of Moores Cancer Center.