p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi

Xiaochao Tan; Priyam Banerjee; Lei Shi; Guan Yu Xiao; B. Leticia Rodriguez; Caitlin L. Grzeskowiak; Xin Liu; Jiang Yu; Don L. Gibbons; William K. Russell; Chad J. Creighton; Jonathan M. Kurie

doi:10.1126/sciadv.abf4885

p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi

Xiaochao Tan, Priyam Banerjee, Lei Shi, Guan Yu Xiao, B. Leticia Rodriguez, Caitlin L. Grzeskowiak, Xin Liu, Jiang Yu, Don L. Gibbons, William K. Russell, Chad J. Creighton, Jonathan M. Kurie

Toxicology and Cancer Biology

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English
Article number	eabf4885
Journal	Science advances
Volume	7
Issue number	25
DOIs	https://doi.org/10.1126/sciadv.abf4885
State	Published - Jun 2021

Bibliographical note

Funding 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

Publisher Copyright:
© 2021 The Authors.

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1126/sciadv.abf4885

Cite this

@article{8b7dfae1d80a4cf6bcab5e3f28497ebc,

title = "p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi",

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.",

author = "Xiaochao Tan and Priyam Banerjee and Lei Shi and Xiao, {Guan Yu} and Rodriguez, {B. Leticia} and Grzeskowiak, {Caitlin L.} and Xin Liu and Jiang Yu and Gibbons, {Don L.} and Russell, {William K.} and Creighton, {Chad J.} and Kurie, {Jonathan M.}",

note = "Funding 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 Publisher Copyright: {\textcopyright} 2021 The Authors.",

year = "2021",

month = jun,

doi = "10.1126/sciadv.abf4885",

language = "English",

volume = "7",

number = "25",

}

TY - JOUR

T1 - p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi

AU - Tan, Xiaochao

AU - Banerjee, Priyam

AU - Shi, Lei

AU - Xiao, Guan Yu

AU - Rodriguez, B. Leticia

AU - Grzeskowiak, Caitlin L.

AU - Liu, Xin

AU - Yu, Jiang

AU - Gibbons, Don L.

AU - Russell, William K.

AU - Creighton, Chad J.

AU - Kurie, Jonathan M.

N1 - Funding 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 Publisher Copyright: © 2021 The Authors.

PY - 2021/6

Y1 - 2021/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85108333475&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85108333475&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abf4885

DO - 10.1126/sciadv.abf4885

M3 - Article

C2 - 34144984

AN - SCOPUS:85108333475

VL - 7

JO - Science advances

JF - Science advances

IS - 25

M1 - eabf4885

ER -

p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this