Cancer invasion: reciprocity between the extracellular matrix and intrinsic ERK signaling

癌症侵袭：细胞外基质和内在 ERK 信号传导之间的相互作用

• 批准号: 10367122
• 负责人: Michelle Christine Mendoza
• 金额: $ 39.84万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367122
• 关键词: Actins; Adenocarcinoma Cell; Affect; American; Basic Science; Biological Assay; Biosensor; Carcinoma; Cell Line; Cell physiology; Cells; Computer Models; Data; Development; Disease; Dyspnea; Embryo; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Foundations; Glioma; Goals; HSV glycoprotein C; Human; Human Cell Line; Immunofluorescence Immunologic; In Situ; In Vitro; Integrins; Intervention; Isogenic transplantation; Knowledge; Lesion; Lung; Lung Adenocarcinoma; Lung Neoplasms; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Membrane; Mesenchymal; Messenger RNA; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Myofibroblast; Neoplasm Metastasis; Nodule; Oncogenic; Operative Surgical Procedures; Outcome; PTK2 gene; Pain; Pathway interactions; Patients; Periodicity; Phosphorylation; Phosphorylation Site; Phosphotransferases; Process; Production; Public Health; Radio; Ras/Raf; Recurrence; Regulation; Research; Respiration; Sampling; Signal Transduction; Slice; Source; Spatial Distribution; Stains; Stimulus; Stretching; Tenascin; Testing; The Cancer Genome Atlas; Tissues; Tumor Cell Invasion; Work; Xenograft procedure; base; cancer cell; cell motility; ezrin; flexibility; improved; in vivo; innovation; mortality; mouse model; mutant; neoplastic cell; novel therapeutics; pancreatic cancer model; prevent; prognostic; prognostic value; programs; response; targeted treatment; tumor; tumor growth; tumor initiation

Cancer cell invasion is the major cause of lung cancer morbidity. Invasion remain untargeted, in part due to an incomplete understanding of the molecular underpinnings of the cellular process. The long-term goal is to identify the mechanisms that drive lung adenocarcinoma invasion. The overall objective here is to elucidate the Tenascin-C and ERK signaling mechanisms that drive LUAD invasion. The central hypothesis is that ERK and Tenascin-C work together to induce LUAD invasion. This is based on our preliminary data. We show that Tenascin-C is expressed early after tumor initiation by activating upstream mutations in the ERK pathway. We also show that Tenascin-C and ERK are both expressed at the invasive edge of tumors, and that Tenascin-C induces ERK activity and ERK-dependent tumor cell invasion in vitro. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the cell source and stimulus for Tenascin-C production in early LUAD, 2) Determine the mechanism by which Tenascin-C signals to LUAD tumor cells, and 3) Identify mechanisms of ERK-mediated LUAD invasion. Under the first aim, we will test if fibroblasts produce Tenascin-C in response to increased strain. In aim 2, we will determine if Tenascin-C signals to induce tumor cell invasion by activating tumor cell integrins and ERK. In aim 3, we will test if LOK/Ezrin are critical ERK effectors that drive the mesenchymal-mode invasion observed in LUAD. This will determine the mechanisms by which the lung cancer extracellular matrix interacts with oncogenic RAS/ERK signaling to drive invasion. The research proposed in this application is innovative, because it tests a new model of Tenascin-C induction, develops a computation model of tumor growth within the lung and under stretch, uses organotypic cultures, and tests a new, druggable ERK effector in the invasion process. The proposed research is significant because it is expected to advance our understanding of lung cancer with new knowledge of how mechanochemical signaling between the stroma and cancer confers cancer invasion. Ultimately, such knowledge has the potential to provide strong scientific justification for the development of new therapies to target invasion and reduce lung cancer morbidity and mortality.

癌细胞侵袭是肺癌发病的主要原因。入侵仍然没有目标，部分原因是 对细胞过程的分子基础的不完全理解。长期来看 目标是确定驱动肺腺癌侵袭的机制。这里的总体目标是 阐明驱动 LUAD 入侵的 Tenascin-C 和 ERK 信号传导机制。中央 假设是 ERK 和 Tenascin-C 共同作用诱导 LUAD 入侵。这是基于我们的 初步数据。我们发现 Tenascin-C 在肿瘤发生后早期通过激活表达 ERK 通路上游突变。我们还表明 Tenascin-C 和 ERK 均表达于 Tenascin-C 诱导 ERK 活性和 ERK 依赖性肿瘤细胞 体外侵袭。将通过追求三个具体目标来检验中心假设：1）确定 早期 LUAD 中腱蛋白-C 产生的细胞来源和刺激，2) 确定其机制 Tenascin-C 向 LUAD 肿瘤细胞发出信号，3) 确定 ERK 介导的 LUAD 侵袭的机制。 第一个目标是，我们将测试成纤维细胞是否会因应变增加而产生腱蛋白-C。瞄准目标 2、我们将确定Tenascin-C是否通过激活肿瘤细胞整合素发出信号来诱导肿瘤细胞侵袭 和ERK。在目标 3 中，我们将测试 LOK/Ezrin 是否是驱动间充质模式的关键 ERK 效应器 LUAD 中观察到入侵。这将确定肺癌细胞外的机制 基质与致癌 RAS/ERK 信号相互作用以驱动侵袭。本文提出的研究 应用程序是创新的，因为它测试了 Tenascin-C 感应的新模型，开发了计算 肺内和拉伸下的肿瘤生长模型，使用器官型培养物，并测试了一种新的、 侵袭过程中可药物化的ERK效应子。拟议的研究意义重大，因为它 预计通过机械化学如何作用的新知识来增进我们对肺癌的理解 基质和癌症之间的信号传递导致癌症侵袭。最终，这些知识具有 有可能为开发针对侵袭的新疗法提供强有力的科学依据 并降低肺癌的发病率和死亡率。