Role of SOX9 mammary stem cell factor in metastasis

项目概要（项目2） 转移仍然是癌症治疗中的一个关键问题。虽然转移的早期步骤 级联反应已被充分表征，转移后期步骤的机制包括 远端部位的外渗、存活和生长仍知之甚少。乳腺癌是一种 异质性疾病由功能多样的癌细胞组成，其中少数 细胞亚群具有高度致瘤性并显示出干细胞样特性。这些干细胞样细胞是 据信可驱动肿瘤在远端部位的再生和传播。然而，基因程序 控制转移中癌症干性的机制仍有待确定。主要监管者 正常的干细胞程序被认为被 CSC 劫持了。我们和其他人最近 确定转录因子 SOX9 是干性的关键调节因子，有助于 转移。使用表达新型 SOX9 报告基因的乳腺肿瘤模型，我们发现 SOX9 高的癌细胞具有丰富的肿瘤启动和转移启动能力。 有趣的是，相对于早期转移瘤，早期转移瘤含有较高频率的 SOX9 高 CSC。 原发性肿瘤，表明转移生态位促进 CSC 扩张或诱导，从而导致 远处转移。然而，调节 SOX9- 的确切细胞内在/外在机制 介导的干性和有助于转移生长的信号通路 SOX9 的下游仍然未知。我们的初步数据确定了 ROS 的新作用- 上调 HIF1a 诱导 SOX9 表达。此外，项目 1 和 3 的结果表明 癌症-基质细胞相互作用通过旁分泌/近分泌信号促进干性。基于 根据累积的初步证据，我们假设 SOX9 驱动的干性是 由转移生态位中的内在和外在信号增强，导致 外渗和转移性生长。我们将确定 ROS/HIF1a 信号传导在 增强 SOX9 驱动的干性（目标 1），了解旁分泌/近分泌信号如何 巨噬细胞和血小板调节 SOX9 驱动的干性（目标 2），并定义下游 介导 SOX9 在外渗和转移生长中作用的途径（目标 3）。

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).