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

Recurrent breast cancer accounts for most disease-associated mortality and can develop decades after primary tumor therapy. Recurrences arise from residual tumor cells (RTC) that can evade therapy in a dormant state; however, the mechanisms enforcing dormancy in RTCs are poorly understood. CRISPR-Cas9 screening identified the transcription factors SOX5 and SOX6 as functional regulators of tumor recurrence. Loss of SOX5 accelerated recurrence at both local and metastatic sites and promoted dormancy escape in both therapy-associated and microenvironment-induced contexts. Remarkably, SOX5 drove dormant RTCs to adopt a cartilage-dependent bone development program, termed endochondral ossification, which was confirmed by [18F]NaF-positron emission tomography (PET) imaging and reversed in recurrent tumors escaping dormancy. Consistent with findings in mice, osteochondrogenic expression signatures in patients were enriched in residual disease following neoadjuvant therapy, and their enrichment in primary breast cancers predicted improved recurrence-free survival. These findings identify SOX5-dependent mesodermal transdifferentiation as an adaptive mechanism that prevents recurrence by reinforcing tumor cell dormancy. SIGNIFICANCE: Our study reveals a SOX5-mediated endochondral ossification program that maintains transdifferentiated breast cancer RTCs in a dormant state and predicts recurrence risk. Incorporating [18F]NaF-PET as an imaging-based readout of this process could stratify patients for minimal residual disease-targeting or dormancy-enforcing treatments, offering a transformative approach to personalize care for breast cancer survivors. See related commentary by Gonçalves and Correia, p. 626.