Mechanisms for Salivary Tumor Epithelial-Mesenchymal Transitions

恶性唾液腺癌是人类健康的主要挑战，因为其高复发率、远处转移和复发率低。 转移，以及很少的治疗选择。关于上皮间质转化的影响知之甚少 (EMT)唾液腺肿瘤发生和治疗分层的分子事件。我们最近出版的 研究证明了一种独特的小鼠模型，其含有致癌Ras转基因，其表达是 条件性诱导仅在表达弹性蛋白酶1（Ela）的下颌下腺导管细胞中 （SMG）。致癌RAS的表达可迅速将正常SMG转化为类似人类的肿瘤 肉瘤样SDC在几乎所有小鼠中在24天内。初步数据表明，活化转化 生长因子β（TGFβ）信号传导和细胞外基质（ECM）组分和整合素的重塑 信号传导可以作为潜在的治疗靶点。我们的总体假设是致癌RAS激活 与TGFβ介导的EMT协同作用，有助于侵袭性和快速生长的肉瘤样SDC， 因此，靶向TGFβ信号传导或抑制ECM下游信号传导代表了合理的 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的信号，并确定可能作为治疗的干预点。 用于治疗肉瘤样SDC的药物靶点。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导管上皮肉瘤样瘤的机制 转化并验证人类肿瘤中的发现。目标二。为了确定TGFβ受体活化是否是 促进致癌RAS介导的EMT，因此，如果TGFβ抑制代表一种治疗策略， 涎腺肉瘤样癌目标3。为了评估ECM组件与 整合素和整合素连接激酶（ILK）在肉瘤样SDC发展过程中的作用。在本申请中，我们提出 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 小的致瘤细胞亚群具有在体内重新增殖和扩增肉瘤样肿瘤的能力？ 如果是的话，我们能不能将它们与剩余的没有这种能力的肿瘤细胞进行比较？如何 富含TGFβ的SMG微环境小生境或ECM重塑是否促进致癌RAS驱动的 肉瘤样SDC？表征参与TGFβ介导的EMT活化和/或 肿瘤细胞-ECM的相互作用将为唾液腺癌的生物学机制提供新的见解 并使我们能够识别潜在的治疗靶点。这关系到我们对 唾液腺肿瘤生物学该项目意义重大，因为它将揭示促进获得 EMT或肉瘤样表型可转化为人类癌症。这个项目是创新的，因为 它将提供对肿瘤微环境（例如，TGFβ，ECM）和 在肉瘤样SDC肿瘤或一般EMT获得的发展过程中致癌RAS信号传导。

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.