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.
|State||Published - Jun 2021|
Bibliographical noteFunding Information:
Anderson Cancer Center) for manuscript editing. We thank Y.-H. Ahn (Ewha Womans University, Republic of Korea) for insightful discussions. Funding: This work was supported by the NIH (R01 CA181184 and CA2111125 to J.M.K. and R37CA214609 to D.L.G.) the UT Lung Cancer SPORE NCI P50 CA070907 (to J.M.K. and D.L.G.), and philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program (to D.L.G.). The UTMB Mass Spectrometry Facility is supported in part by CPRIT grant RP190682 (to W.K.R.). J.M.K. holds the Gloria Lupton Tennison Distinguished Endowed Professorship in Lung Cancer. Author contributions: X.T. conceived, designed, executed, and interpreted the molecular biology, cell culture, and in vivo experiments. P.B. conceived, designed, executed, and interpreted the experiments to assess protein colocalization by confocal microscopy. L.S. assisted X.T. with Western blot experiments. C.L.G. generated the PAQR11-Cre virus. X.L. assisted X.T. with the in vivo experiments. B.L.R. and X.L. performed the immune cell profiling study. D.L.G. supervised the immune cell profiling assays. G.-Y.X. conceived and interpreted the RAB6A vesicle imaging and quantification work. J.Y. bred the
© 2021 The Authors.
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