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

doi:10.1172/JCI137186

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 journal › Article › peer-review

35 Scopus citations

Abstract

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 language	English
Article number	e137186
Journal	Journal of Clinical Investigation
Volume	131
Issue number	1
DOIs	https://doi.org/10.1172/JCI137186
State	Published - Jan 4 2021

Bibliographical note

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

Funding

We thank Fengju Chen for technical assistance. This work was supported by the NIH through R01 CA181184 (to JMK), R01 CA2111125 (to JMK), P30 CA125123 (to CJC), K99 CA225633 (to HFG), and Lung Cancer Research Foundation FP 00005299 (to XT). JMK holds the Gloria Lupton Tennision Distinguished Endowed Professorship in Lung Cancer. DLG is an R. Lee Clark Fellow of the University of Texas MD Anderson Cancer Center, supported by the Jeane F. Shelby Scholarship Fund. The work was also supported by the generous philanthropic contributions to the University of Texas MD Anderson Lung Cancer Moon Shots Program.

Funders	Funder number
Jeane F. Shelby Scholarship Fund
National Institutes of Health (NIH)	R01 CA2111125, K99 CA225633, P30 CA125123
National Childhood Cancer Registry – National Cancer Institute	R01CA181184
Lung Cancer Research Foundation	FP 00005299
University of Texas Anderson Cancer Center

ASJC Scopus subject areas

General Medicine

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

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10.1172/JCI137186

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title = "A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma",

abstract = "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.",

author = "Xiaochao Tan and Lei Shi and Priyam Banerjee and Xin Liu and Guo, \{Hou Fu\} and Jiang Yu and Neus Bota-Rabassedas and Rodriguez, \{B. Leticia\} and Gibbons, \{Don L.\} and Russell, \{William K.\} and Creighton, \{Chad J.\} and Kurie, \{Jonathan M.\}",

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doi = "10.1172/JCI137186",

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AU - Banerjee, Priyam

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AU - Guo, Hou Fu

AU - Yu, Jiang

AU - Bota-Rabassedas, Neus

AU - Rodriguez, B. Leticia

AU - Gibbons, Don L.

AU - Russell, William K.

AU - Creighton, Chad J.

AU - Kurie, Jonathan M.

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A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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