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关键问题。虽然转移的早期步骤 级联反应的特点是，机制的后期步骤转移，包括 外渗、远端部位的存活和生长仍然知之甚少。乳腺癌是一 异质性疾病包括功能多样的癌细胞，其中一个小的 细胞亚群具有高度致瘤性并显示干细胞样特性。这些干细胞是 据信可促使肿瘤在远端部位再生长和扩散。然而，基因工程 控制癌细胞转移的干细胞因子仍有待确定。的主要监管机构 正常的干细胞程序被认为是被CSC劫持的。我们和其他人最近 确定了转录因子SOX 9作为干细胞的关键调节因子， 转移使用表达新型SOX 9报告基因的乳腺肿瘤模型，我们发现， S 0X 9高的癌细胞富含肿瘤起始和转移起始能力。 有趣的是，早期转移瘤中含有高频率的SOX 9-高CSC，相对于正常对照组， 原发性肿瘤，表明转移性小生境促进CSC扩增或诱导，导致 远处转移然而，调控SOX 9的确切的细胞内在/外在机制， 介导的干性和有助于转移性生长的信号通路 SOX 9的下游仍然未知。我们的初步数据确定了ROS的新作用- 上调HIF 1a诱导SOX 9表达。此外，项目1和3的结果表明， 癌-基质细胞相互作用通过旁分泌/旁分泌信号促进干性。基于 根据累积的初步证据，我们假设SOX 9驱动的干性是 通过转移性小生境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/HIF 1a信号转导的作用， 增强SOX 9驱动的干性（目标1），了解旁分泌/旁分泌信号如何从 巨噬细胞和血小板调节SOX 9驱动的干性（目的2），并定义下游 在外渗和转移性生长中介导SOX 9作用的途径（目的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).