Mechanisms for Salivary Tumor Epithelial-Mesenchymal Transitions

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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.