Residual Breast Cancer Cells Co-opt SOX5-Driven Endochondral Ossification to Maintain Dormancy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Recurrent breast cancer is a major cause of cancer mortality.
• Mechanisms of residual tumor cell (RTC) dormancy are poorly understood.
• RTCs can evade therapy and cause late recurrences.

Purpose of the Study:

• To identify regulators of RTC dormancy and recurrence.
• To investigate the role of SOX5/6 transcription factors in breast cancer recurrence.
• To elucidate the mechanisms by which RTCs escape dormancy.

Main Methods:

• CRISPR-Cas9 screening to identify functional regulators of tumor recurrence.
• In vivo studies in mice to assess the impact of SOX5 loss on recurrence.
• [18F]NaF-PET imaging to confirm endochondral ossification.
• Analysis of patient data to correlate gene expression with recurrence-free survival.

Main Results:

• CRISPR-Cas9 screening identified SOX5/6 as key regulators of tumor recurrence.
• Loss of SOX5 accelerated both local and metastatic recurrence.
• SOX5 promotes dormancy by inducing an endochondral ossification program in RTCs.
• Osteochondrogenic signatures in patients predict improved recurrence-free survival.

Conclusions:

• SOX5-dependent mesodermal transdifferentiation reinforces tumor cell dormancy, preventing recurrence.
• SOX5 plays a critical role in maintaining RTC dormancy.
• Targeting SOX5 or related pathways may offer new therapeutic strategies for preventing breast cancer recurrence.