2. Academic Validation
  3. p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi

p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi

  • Sci Adv. 2021 Jun 18;7(25):eabf4885. doi: 10.1126/sciadv.abf4885.
Xiaochao Tan 1,  Priyam Banerjee 2,  Lei Shi 2,  Guan-Yu Xiao 2,  B Leticia Rodriguez 2,  Caitlin L Grzeskowiak 3 4,  Xin Liu 2,  Jiang Yu 2,  Don L Gibbons 2,  William K Russell 5,  Chad J Creighton 4 6,  Jonathan M Kurie 1
Affiliations

Affiliations

  • 1 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected] [email protected].
  • 2 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Department of Molecular and Human Genetics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 4 Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 5 Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
  • 6 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
PMID: 34144984 DOI: 10.1126/sciadv.abf4885
Abstract

Cancer cells exhibit hyperactive secretory states that maintain Cancer cell viability and remodel the tumor microenvironment. However, the oncogenic signals that heighten secretion remain unclear. Here, we show that p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi. p53 loss up-regulates the expression of a Golgi scaffolding protein, progestin and adipoQ receptor 11 (PAQR11), which recruits an adenosine diphosphate ribosylation factor 1-containing protein complex that loads cargos into secretory vesicles. PAQR11-dependent secretion of a protease, PLAU, prevents anoikis and initiates autocrine activation of a PLAU receptor/signal transducer and activator of transcription-3-dependent pathway that up-regulates PAQR11 expression, thereby completing a feedforward loop that amplifies prometastatic effector protein secretion. Pharmacologic inhibition of PLAU receptor impairs the growth and metastasis of p53-deficient cancers. Blockade of PAQR11-dependent secretion inhibits immunosuppressive processes in the tumor microenvironment. Thus, Golgi reprogramming by p53 loss is a key driver of hypersecretion in Cancer.

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