Role of SOX9 mammary stem cell factor in metastasis

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Project Summary (Project 2) Metastasis remains a critical problem in cancer treatment. While the early steps of the metastatic cascade are well-characterized, the mechanisms underlying late steps of metastasis, including extravasation, survival and growth at distal sites, remain poorly understood. Breast cancer is a heterogeneous disease comprised of functionally diverse cancer cells, among which a minor subset of cells is highly tumorigenic and shows stem-like properties. These stem-like cells are believed to drive tumor regrowth and propagation at the distal sites. However, genetic programs that control cancer stemness in metastasis remain to be determined. The master regulators of normal stem cell programs are thought to be hijacked by CSCs. We and others have recently identified the transcription factor SOX9 as a key regulator for stemness that contributes to metastasis. Using mammary tumor models expressing a novel SOX9 reporter, we found that SOX9-high cancer cells are enriched in tumor-initiating and metastasis-initiating abilities. Interestingly, early-stage metastases contain a high frequency of SOX9-high CSCs relative to primary tumors, suggesting the metastatic niche promotes CSC expansion or induction leading to distant metastasis. However, the exact cell-intrinsic/-extrinsic mechanisms that regulate SOX9- mediated stemness and the signaling pathways that contribute to metastatic outgrowth downstream of SOX9 remain unknown. Our preliminary data identified a novel role of ROS- upregulated HIF1a in inducing SOX9 expression. In addition, results from Project 1 and 3 suggest that cancer-stromal cell interactions promote stemness through paracrine/juxtacrine signals. Based on the cumulative preliminary evidence, we hypothesize that SOX9-driven stemness is potentiated by intrinsic and extrinsic signals in the metastatic niche, leading to extravasation and metastatic outgrowth. We will determine the role of ROS/HIF1a signaling in potentiating SOX9-driven stemness (Aim 1), understand how paracrine/juxtacrine signals from macrophages and platelets regulate SOX9-driven stemness (Aim 2), and define the downstream pathways mediating the action of SOX9 in extravasation and metastatic growth (Aim 3).