Residual Breast Cancer Cells Co-opt SOX5-Driven Endochondral Ossification to Maintain Dormancy
Menée à l'aide de modèles murins de cancer mammaire et d'une technique de criblage génétique utilisant la technologie d'édition CRISPR Cas9, cette étude met en évidence un mécanisme par lequel le facteur de transcription SOX5 maintient la dormance des cellules cancéreuses résiduelles en favorisant l'adoption par ces dernières d'un programme de développement osseux appelé ossification endochondrale
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
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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.
Cancer Discovery , résumé, 2026