Loss of Sox10 in a HER2+ model prevents tumor initiation and induces luminal-to-basal reprograming in cancer cells.

Abstract

The SRY-HMG-Box transcription factor SOX10 plays a critical role in neural crest development, but its function in epithelial tumorigenesis remains unclear. Here, we identify SOX10 as a key regulator of tumor-initiating activity in Neu-driven mammary cancers. Genetic ablation of Sox10 in the luminal compartment of MMTV-Neu (NIC) mice resulted in delayed but normal mammary gland development. Sox10 deletion resulted in a reduction in mammary progenitors and tumor initiating activity with a complete loss of tumor initiation in Sox10-deficient luminal cells. CRISPR/Cas9-mediated Sox10 inactivation in Neu-transformed tumor cells led to diminished self-renewal in mammosphere assays, markedly impaired growth in orthotopic transplant models and profoundly reduced lung colonization following tail vein injection, suggesting a depletion of cancer stem cell activity. Transcriptomic profiling revealed that Sox10-deficiency in Neu+ tumor cells induces a luminal-to-basal/stem-like shift and the downregulation of several genes associated with genetic networks regulating stemness. Collectively, these findings demonstrate that Sox10 is required for a permissive luminal cell state for Neu-driven tumor initiation and that it is critical for cancer stem cell activity and the establishment of metastases. SignificanceThe Sox10 transcription factor is critical for mammary stem cell function and plasticity. Animal studies suggest that different subtypes of breast cancers arise from luminal epithelial cells and hypothesized the implication of luminal stem cells in breast cancer initiation. We show that Sox10 deletion in the luminal compartment of adult female mice abrogates tumor initiation. Sox10 inactivation impairs tumor cell growth, dissemination and reprograms luminal Neu+ tumor cells to a basal phenotype. Our data supports a model whereby luminal progenitors are required for tumor initiation, self-renewal and growth at distant sites. The findings suggest that therapies aimed at interfering with Sox10 activity or expression might be beneficial in the treatment of breast cancers.