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：
10277847
负责人：
Jonathan M Kurie
金额：
$ 43.39万
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/10277847
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 cancer cell cohort design improved inhibitor/antagonist 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.

癌细胞嵌入受保护和滋养的“利基”中，通过将蛋白质分泌到周围环境中，癌细胞创造的环境。因为癌细胞依靠他们的利基来生存并传播到身体其他部位，我们认为抑制秘密可以抑制癌症的扩散，从而改善癌症患者的长度和质量居住。开发这种疗法将需要更好地了解癌症中分泌的激活。我们的提案将解决这一知识差距。在这里，我们表明p53蛋白质丧失是癌症的既定驱动力扩散，通过重新编程高尔基仪器（Golgi Appratus）来增强分泌，这是蛋白质转运的主要调节剂细胞。我们表明p53损失激活了控制分泌的高尔基蛋白复合物的形成，我们已经确定了对肺癌生长和扩散至关重要的分泌蛋白质。此外，我们还有鉴定出可以阻止高尔基蛋白复合物形成，减少分泌并抑制肺的药物癌症的生长和扩散。在此应用中，我们试图阐明分子基础和由p53损失驱动的增强分泌的治疗意义。在AIM 1中，我们建议研究阐明高尔基蛋白复合物如何增强分泌并驱动肺癌的进展。在AIM 2中，我们建议研究确定高尔基蛋白复合物如何增加对药物的敏感性确定。这些研究将提供有关癌症分泌如何激活的洞察力，并可能导致新的靶向癌症患者分泌的方法。