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

• 批准号: 10656365
• 负责人: Jonathan M Kurie
• 金额: $ 46.76万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/10656365
• 关键词: 1-Phosphatidylinositol 4-Kinase; Acceleration; 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; Dedications; Development; Docking; Ectopic Expression; Endoplasmic Reticulum; Environment; Enzymes; GOLPH3 gene; GORASP2 gene; Genetic; Golgi Apparatus; Growth; Human; Hydrophobicity; Immunosuppression; KRASG12D; Knowledge; 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; 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; novel therapeutic intervention; pharmacologic; programs; protein complex; protein transport; small hairpin RNA; small molecule; therapeutically effective; therapy design; tool; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenic; vesicle transport

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.

癌细胞被嵌入到一个保护性和滋养性的“利基”中，一个 癌细胞通过将蛋白质分泌到周围环境中而创造的环境。因为癌细胞 依靠它们的利基生存并传播到身体的其他部位，我们相信旨在 抑制分泌可以抑制癌症的扩散，从而提高癌症患者的体型和质量。 活着。开发这样的疗法需要更好地了解癌症中分泌是如何被激活的。我们的 提案将解决这一知识差距。我们在这里展示了P53蛋白丢失，这是癌症的既定驱动因素 通过重新编程高尔基体，促进分泌，高尔基体是蛋白质运输的主要调节器 细胞。我们发现，P53的丢失激活了控制分泌的高尔基体蛋白复合体的形成，而我们 已经确定了对肺癌生长和扩散至关重要的分泌蛋白。此外，我们还拥有 确定了一种可以阻断高尔基蛋白复合体的形成、减少分泌和抑制肺的药物 癌症的生长和扩散。在这一应用中，我们试图阐明分子基础和 P53基因缺失引起的分泌量增加的治疗意义。在目标1中，我们建议进行以下研究 阐明高尔基蛋白复合体是如何促进分泌和推动肺癌进展的。在目标2中，我们 建议进行研究，以确定高尔基蛋白复合体如何增加对我们所拥有的药物的敏感性 确认身份。这些研究将提供对癌症中分泌物如何被激活的洞察力，并可能导致新的 针对癌症患者分泌物的方法。