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: 10745809
• 负责人: Michelle Christine Mendoza
• 金额: $ 3.29万
• 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/10745809
• 关键词: Actins; Adenocarcinoma Cell; Affect; American; Award; 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; Invaded; 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; Parents; Pathway interactions; Patients; Periodicity; Phosphorylation; Phosphorylation Site; Phosphotransferases; Process; Production; Public Health; Radiation therapy; 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; 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

PROJECT SUMMARY - from parent award 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.

项目摘要-来自母公司的奖励 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 目的是确定驱动肺腺癌侵袭的机制。总体目标是 阐明Tenascin-C和ERK信号转导机制，驱动LUAD入侵。中央 假设ERK和生腱蛋白-C共同作用以诱导LUAD侵袭。这是基于我们 初步数据。我们发现腱生蛋白-C在肿瘤发生后早期表达， ERK通路的上游突变。我们还表明，Tenascin-C和ERK都表达在 腱生蛋白C诱导ERK活性和ERK依赖性肿瘤细胞 体外侵袭。中心假设将通过追求三个具体目标进行测试：1）确定 细胞来源和早期LUAD中生腱蛋白-C产生的刺激，2）确定 生腱蛋白-C向LUAD肿瘤细胞发出信号，以及3）鉴定ERK介导的LUAD侵袭的机制。 在第一个目标下，我们将测试成纤维细胞是否响应于增加的应变而产生生腱蛋白-C。在aim中 2.我们将确定腱生蛋白-C是否通过激活肿瘤细胞整合素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效应子。 在LUAD中观察到入侵。这将决定肺癌细胞外 基质与致癌RAS/ERK信号相互作用以驱动侵袭。这项研究提出， 应用是创新的，因为它测试了一种新的Tenascin-C诱导模型，开发了一种计算方法， 肺内肿瘤生长模型和拉伸下，使用器官型培养，并测试一种新的， 在侵袭过程中可药物化的ERK效应子。这项研究之所以重要，是因为 预计将通过机械化学如何影响肺癌的新知识， 间质和癌之间的信号传递赋予癌侵袭。最终，这些知识 有可能为靶向侵袭的新疗法的开发提供强有力的科学依据 降低肺癌发病率和死亡率。