A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma

Therapeutic strategies designed to target TP53-deficient cancer cells remain elusive. Here, we showed that TP53 loss initiated a pharmacologically actionable secretory processthat 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.

Automated summary

Loss of TP53 initiates a pharmacologically actionable secretory process in lung adenocarcinoma (LUAD) cells. Activation of G55-dependent secretion promotes proliferation and invasion of TP53-deficient LUAD cells. Targeting the G55-G45 interaction with a small molecule impairs secretion and reduces growth and metastasis of TP53-deficient LUAD.