Mechanisms for Salivary Tumor Epithelial-Mesenchymal Transitions

恶性涎癌是对人类健康的一大挑战，因为复发率很高， 转移，几乎没有治疗选择。对上皮间充质转化的影响知之甚少 (EMT)关于唾液肿瘤发生和治疗分层的分子事件。我们最近出版的 研究表明，一种独特的小鼠模型包含致癌的RAS转基因，其表达是 条件性诱导表达弹性蛋白酶1(Ela)的颌下腺导管细胞 (SMGs)。致癌RAS的表达可使正常SMGs迅速转化为与人类相似的肿瘤 几乎所有的小鼠在24天内都有肉瘤样的SDCs。初步数据表明，激活的转化 转化生长因子β信号转导与细胞外基质成分和整合素的重构 信号可能成为潜在的治疗靶点。我们的总体假设是致癌的RAS激活 在与转化生长因子β介导的EMT的合作中，有助于侵袭性和快速生长的肉瘤样SDC， 因此，靶向转化生长因子β信号转导或抑制细胞外基质下游信号转导代表着一种合理化的 治疗SDC的策略。我们的目标是发现肿瘤细胞内的内在因素以及外在因素。 肿瘤微环境中触发EMT并识别干预点的信号可能起到 治疗肉瘤样SDC的可用药靶点。为了实现这一目标，我们提出了三个具体目标：目标1。 建立致癌RAS驱动小鼠SMG导管上皮肉瘤样变的机制 转化和验证人类肿瘤的发现。目的2.确定转化生长因子β受体激活是否是关键 如果抑制转化生长因子β代表了一种治疗策略 唾液肉瘤样癌。目的3.评估ECM组件与 整合素和整合素连接的激酶(ILK)在肉瘤样SDC发展过程中的作用。在此应用程序中，我们建议 使用我们独特的转基因小鼠模型来解决这些关键问题：这些肿瘤细胞是否含有 有能力在体内重新填充和扩大肉瘤样瘤的成瘤细胞的小亚群？ 如果是这样的话，我们能否描述它们的特征，并将它们与剩余的没有这种能力的肿瘤细胞进行比较？多么 转化生长因子β丰富的SMG微环境或细胞外基质重塑是否推动致癌RAS驱动 肉瘤样SDC？转化生长因子β介导的EMT激活和/或信号转导通路的特征 肿瘤细胞与细胞外基质的相互作用将为涎癌发生的生物学机制提供新的见解 并使我们能够确定潜在的治疗靶点。这与我们对 唾液肿瘤生物学。这个项目意义重大，因为它将揭示促进收购 可转化为人类癌症的EMT或肉瘤样表型。这个项目是创新的，因为 它将为肿瘤微环境(如转化生长因子β)和细胞外基质之间的串扰提供新的见解 肉瘤样SDC肿瘤发生或EMT获得过程中致癌RAS信号转导。

Malignant salivary cancers are a major challenge to human health due to high recurrence rates, distant metastases, and few treatment options. Little is known about the impact of epithelial mesenchymal transition (EMT) on the molecular events of salivary tumorigenesis and therapeutic stratifications. Our recent published studies demonstrate a unique mouse model that contains an oncogenic Ras transgene, for which expression is conditionally induced exclusively in elastase 1 (Ela)-expressing ductal cells of the submandibular glands (SMGs). The expression of oncogenic RAS rapidly transforms normal SMGs into tumors resembling human sarcomatoid SDCs within 24 days in almost all mice. Preliminary Data suggests that activated transforming growth factor beta (TGFβ) signaling and remodeling of extracellular matrix (ECM) components and integrin signaling could serve a potential therapeutic target. Our overall hypothesis is that oncogenic RAS activation in cooperation with TGFβ-mediated EMT contributes to aggressive and fast-growing sarcomatoid SDC, thus targeting TGFβ signaling or inhibition of ECM downstream signaling represent a rationalized strategy to treat SDCs. Our goal is to discover the intrinsic factors within tumor cells as well as extrinsic signals in the tumor microenvironment that trigger EMT and identify an intervention point that may serve as a druggable target for treating sarcomatoid SDC. To achieve this goal, we propose three Specific Aims: Aim 1. To establish mechanisms through which oncogenic RAS drives mouse SMG ductal epithelial-sarcomatoid transformation and validate findings in human tumors. Aim 2. To determine if TGFβ receptor activation is a key contributor to oncogenic RAS-mediated EMT and thus if TGFβ inhibition represents a therapeutic strategy for salivary sarcomatoid carcinoma. Aim 3. To evaluate the cooperative interaction of ECM components with integrin and integrin-linked kinase (ILK) during sarcomatoid SDC development. In this application, we propose to use our unique transgenic mouse model to address these key questions: Do these tumor cells contain a small subpopulation of tumorigenic cells with the ability to re-populate and expand sarcomatoid tumors in vivo? If so, can we characterize them and compare them to the remaining tumor cells without this capacity? How does TGFβ-rich SMG microenvironmental niche or ECM remodeling propel oncogenic RAS-driven sarcomatoid SDC? Characterizing the signaling pathways involved in TGFβ-mediated EMT activation and/or tumor cell-ECM interactions will provide novel mechanistic insights into the biology of salivary cancer initiation and expansion and allow us to identify potential therapeutic targets. This is relevant to our understanding of salivary tumor biology. This project is significant, as it will uncover mechanisms that promote the acquisition of EMT or sarcomatoid phenotypes that can be translated to human cancers. This project is innovative, because it will provide novel insight into the crosstalk between tumor microenvironment (e.g., TGFβ, the ECM) and oncogenic RAS signaling during the development of sarcomatoid SDC tumors or EMT acquisition in general.