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A pro-metastatic secretory pathway activated by p53 loss in lung cancer

肺癌中 p53 缺失激活的促转移分泌途径

基本信息

批准号：
10440513
负责人：
Jonathan M Kurie
金额：
$ 42.53万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10440513
关键词：
1-Phosphatidylinositol 4-Kinase Address Adenocarcinoma Cell Adhesions Autophagocytosis Autophagosome Binding Proteins Binding Sites Biogenesis Biological Body part Bypass CD8-Positive T-Lymphocytes Cancer Patient Cell membrane Cells Clinical Complex Conditioned Culture Media Development Docking Ectopic Expression Endoplasmic Reticulum Environment Enzymes GOLPH3 gene GORASP2 gene Genetic Golgi Apparatus Growth Human Hydrophobicity Immunosuppression KRASG12D Knowledge Lead Length Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Molecular Mus Mutation N-terminal Neoplasm Metastasis Oncogenes PIK4CB gene Pathway interactions Peptide Signal Sequences Peptide Transport Pharmaceutical Preparations Pharmacology Play Primary Neoplasm Process Property Protein Secretion Proteins Receptor Protein-Tyrosine Kinases Regulatory Pathway Sampling Stress Surface TP53 gene Testing Therapeutic Tissues Tumor Burden Vesicle angiogenesis antagonist cancer cell cohort design improved inhibitor insight liquid chromatography mass spectrometry metastatic process mouse model mutant novel programs protein complex protein transport small hairpin RNA small molecule therapeutically effective therapy design tool treatment strategy tumor tumor growth tumor microenvironment tumor progression tumorigenic vesicle transport

项目摘要

Cancer cells are embedded in a protective and nourishing “niche”, an environment that cancer cells create by secreting proteins into their surroundings. Because cancer cells depend on their niche to survive and spread to other parts of the body, we believe that therapies designed to inhibit secretion could suppress cancer spread and thereby improve the length and quality of cancer patients' lives. Developing such therapies will require a better understanding of how secretion is activated in cancer. Our proposal will address this knowledge gap. Here we show that p53 protein loss, an established driver of cancer spread, enhances secretion by reprogramming the Golgi apparatus, a master regulator of protein transport in cells. We show that p53 loss activates the formation of a Golgi protein complex that controls secretion, and we have identified secreted proteins that are essential for lung cancer growth and spread. Furthermore, we have identified a drug that can block the formation of the Golgi protein complex, reduce secretion, and inhibit lung cancer growth and spread. In this application, we seek to elucidate the molecular underpinnings and therapeutic implications of the heightened secretion driven by p53 loss. In aim 1, we propose studies to elucidate how the Golgi protein complex enhances secretion and drives lung cancer progression. In aim 2, we propose studies to determine how the Golgi protein complex increases sensitivity to the drug we have identified. These studies will provide insight into how secretion is activated in cancer and may lead to new ways to target secretion in cancer patients.

癌细胞被嵌入一个保护和滋养的“生态位”，癌细胞通过分泌蛋白质到周围环境中而产生的环境。因为癌细胞依靠它们的利基生存并扩散到身体的其他部位，我们认为，抑制分泌可以抑制癌症扩散，从而提高癌症患者的寿命和质量。生活开发这种疗法需要更好地了解癌症中分泌是如何被激活的。我们该提案将弥补这一知识差距。在这里，我们表明，p53蛋白的损失，一个既定的驱动程序的癌症，扩散，通过重新编程高尔基体来增强分泌，高尔基体是蛋白质运输的主要调节器，细胞我们发现p53缺失激活了控制分泌的高尔基体蛋白复合体的形成，已经鉴定出对肺癌生长和扩散至关重要的分泌蛋白。此外，我们还确定了一种药物，可以阻止高尔基体蛋白复合物的形成，减少分泌，并抑制肺癌症的生长和扩散。在本申请中，我们试图阐明分子基础，由p53缺失驱动的分泌增加的治疗意义。在目标1中，我们建议开展研究，阐明高尔基体蛋白复合体如何增强分泌和驱动肺癌进展。在目标2中，我们我建议进行研究，以确定高尔基体蛋白复合物如何增加对我们现有药物的敏感性。鉴定这些研究将提供深入了解分泌是如何在癌症中被激活的，并可能导致新的靶向癌症患者分泌的方法。