A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma

• Published in: The Journal of clinical investigation Vol. 131; no. 1
• Main Authors: Tan, Xiaochao, Shi, Lei, Banerjee, Priyam, Liu, Xin, Guo, Hou-Fu, Yu, Jiang, Bota-Rabassedas, Neus, Rodriguez, B Leticia, Gibbons, Don L, Russell, William K, Creighton, Chad J, Kurie, Jonathan M
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 04.01.2021
• Subjects: Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; Animals; Care and treatment; Cell Line, Tumor; Development and progression; Gene expression; Genetic aspects; Golgi Apparatus - genetics; Golgi Apparatus - metabolism; Golgi Apparatus - pathology; Health aspects; Humans; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Neoplasm Metastasis; Tumor proteins; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - metabolism; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; United States; Oncology; Protein traffic; Lung cancer; Cell Biology; P53
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI137186

Therapeutic strategies designed to target TP53-deficient cancer cells remain elusive. Here, we showed that TP53 loss initiated a pharmacologically actionable secretory process that drove lung adenocarcinoma (LUAD) progression. Molecular, biochemical, and cell biological studies showed that TP53 loss increased the expression of Golgi reassembly and stacking protein 55 kDa (G55), a Golgi stacking protein that maintains Golgi organelle integrity and is part of a GOLGIN45 (G45)-myosin IIA-containing protein complex that activates secretory vesicle biogenesis in the Golgi. TP53 loss activated G55-dependent secretion by relieving G55 and myosin IIA from miR-34a-dependent silencing. G55-dependent secreted proteins enhanced the proliferative and invasive activities of TP53-deficient LUAD cells and promoted angiogenesis and CD8+ T cell exhaustion in the tumor microenvironment. A small molecule that blocks G55-G45 interactions impaired secretion and reduced TP53-deficient LUAD growth and metastasis. These results identified a targetable secretory vulnerability in TP53-deficient LUAD cells.