A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma

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

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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.

Original languageEnglish
Article numbere137186
JournalJournal of Clinical Investigation
Issue number1
StatePublished - Jan 4 2021

Bibliographical note

Publisher Copyright:
© 2021, American Society for Clinical Investigation.

ASJC Scopus subject areas

  • General Medicine


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