A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma |
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| Authors: | Xiaochao Tan Lei Shi Priyam Banerjee Xin Liu Hou-Fu Guo Jiang Yu Neus Bota-Rabassedas B. Leticia Rodriguez Don L. Gibbons William K. Russell Chad J. Creighton Jonathan M. Kurie |
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| Affiliation: | 1.Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;2.Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.;3.Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.;4.Department of Bioinformatics and Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA. |
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| Abstract: | 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. |
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| Keywords: | Cell Biology Oncology |
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