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.

癌细胞嵌入在一个具有保护性和滋养性的“生态位”中，癌细胞通过向周围环境分泌蛋白质而创造的环境。依赖于它们的生存并扩散到身体的其他部位，我们相信旨在治疗的疗法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开发此类疗法需要更好地了解癌症中的分泌是如何激活的。该提案将解决这一知识空白，在这里我们展示了 p53 蛋白的丢失，这是癌症的一个既定驱动因素。传播，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我们发现 p53 缺失会激活控制分泌的高尔基体蛋白复合物的形成，并且我们此外，我们还发现了对肺癌生长和扩散至关重要的分泌蛋白。鉴定出一种药物可以阻断高尔基体蛋白复合物的形成、减少分泌、抑制肺功能在此应用中，我们试图阐明癌症的分子基础和扩散。 p53 缺失导致的令人惊叹的分泌的治疗意义在目标 1 中，我们建议进行研究。在目标 2 中，我们阐明高尔基体蛋白复合物如何增强分泌并驱动肺癌进展。提出研究以确定高尔基体蛋白复合物如何提高我们对药物的敏感性这些研究将深入了解癌症中的分泌如何被激活，并可能导致新的发现。靶向癌症患者分泌的方法。