An actionable secretory program that drives tumor progression in a genetically defined subset of lung squamous carcinoma

一种可操作的分泌程序，可驱动基因定义的肺鳞癌亚群中的肿瘤进展

• 批准号: 10646979
• 负责人: Xiaochao Tan
• 金额: $ 5.93万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2023-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646979
• 关键词: 3q26; ATP phosphohydrolase; Address; Binding; Biochemical; Biogenesis; Cancer Etiology; Cell Line; Cell Survival; Cell membrane; Cells; Cessation of life; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Conditioned Culture Media; Diploidy; Endosomes; Genes; Genetic; Golgi Apparatus; Growth; In Vitro; Induction of Apoptosis; Integral Membrane Protein; Knock-out; Label; Lysosomes; Malignant Epithelial Cell; Malignant neoplasm of lung; Mediating; Mediator; Membrane; Molecular; Mus; Neoplasm Metastasis; Oncogenic; Pathway interactions; Phenocopy; Play; Process; Protein Secretion; Protein Sortings; Proteins; Pump; Role; Sampling; Secretory Vesicles; Shapes; Small Interfering RNA; Somatic Mutation; Squamous Cell Lung Carcinoma; Testing; Therapeutic; Ubiquitin; Work; antitumor effect; cancer cell; cancer type; driver mutation; in vivo; insight; liquid chromatography mass spectrometry; metastatic process; novel therapeutics; patient derived xenograft model; programs; reconstitution; repository; sensor; small hairpin RNA; targeted treatment; trafficking; tumor; tumor microenvironment; tumor progression; tumorigenic

Project Summary Lung cancer is the primary cause of cancer-related death worldwide, with lung squamous cell carcinoma (LUSC) being the second most common subtype. Although LUSC has been characterized by several well-defined driver mutations, including amplifications of chromosomes 3q26, targeted therapy approaches have been unsuccessful so far. Copy number gain or amplification of chromosome 3q occurs in more than 80% of LUSC, while progress has been slow in developing therapeutic strategies to target this specific LUSC subtype. We have identified several Golgi genes in this amplicon, including Golgi Integral Membrane Protein 4 (GOLIM4), which encodes a transmembrane Golgi protein that regulates endosome-to-Golgi trafficking, and ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1), which encodes a Golgi-resident Ca2+/Mn2+ pump that regulates Ca2+-dependent protein sorting and secretion. We found that GOLIM4 and ATP2C1 form a complex on the Golgi and play a fundamental role in LUSC growth and metastasis by promoting the secretion of pro-tumorigenic proteins. In addition, ATP2C1 regulates Mn2+ influx into the Golgi lumen, causing GOLIM4 degradation upon Mn2+ exposure. Mn2+ treatment inhibits the growth of chromosome 3q-amplified LUSC cells in vitro and in vivo. In the proposed work, we will explore how GOLIM4 and ATP2C1 cooperatively modulate the Golgi secretory pathway during LUSC progression and test whether GOLIM4 and ATP2C1 co-amplification creates a therapeutic vulnerability in chromosome 3q-amplified LUSC.

项目概要 肺癌是全球癌症相关死亡的主要原因，其中肺鳞状细胞癌 (LUSC) 是第二常见的亚型。尽管 LUSC 的特点是有几个明确定义的驱动程序 突变，包括染色体 3q26 的扩增，靶向治疗方法一直不成功 迄今为止。超过 80% 的 LUSC 发生拷贝数增加或染色体 3q 扩增，而进展 针对这种特定 LUSC 亚型的治疗策略的制定进展缓慢。我们已经确定 该扩增子中包含多个高尔基体基因，包括高尔基体整合膜蛋白 4 (GOLIM4)，它编码 调节内体到高尔基体运输的跨膜高尔基体蛋白和 ATP 酶分泌途径 Ca2+ 运输 1 (ATP2C1)，编码高尔基体 Ca2+/Mn2+ 泵，调节 Ca2+ 依赖性 蛋白质分选和分泌。我们发现GOLIM4和ATP2C1在高尔基体上形成复合物并发挥作用 通过促进促肿瘤蛋白的分泌，在 LUSC 生长和转移中发挥重要作用。在 此外，ATP2C1 调节 Mn2+ 流入高尔基体腔，导致 Mn2+ 暴露后 GOLIM4 降解。 Mn2+ 处理可抑制体外和体内 3q 染色体扩增的 LUSC 细胞的生长。在提议的 工作中，我们将探讨 GOLIM4 和 ATP2C1 如何协同调节高尔基体分泌途径 LUSC 进展并测试 GOLIM4 和 ATP2C1 共同扩增是否会造成治疗脆弱性 染色体 3q 扩增的 LUSC。