The Akt/mTOR and MNK/eIF4E pathways rewire the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells

Brina, Daniela, Ponzoni, Adele, Troiani, Martina, Calì, Bianca, Pasquini, Emiliano, Attanasio, Giuseppe, Mosole, Simone, Mirenda, Michela, D'Ambrosio, Mariantonietta, Colucci, Manuel, Guccini, Ilaria, Revandkar, Ajinkya, Alajati, Abdullah, Tebaldi, Toma, Donzel, Deborah, Lauria, Fabio, Parhizgari, Nahjme, Valdata, Aurora, Maddalena, Martino, Calcinotto, Arianna, Bolis, Marco, Rinaldi, Andrea, Barry, Simon, Rüschoff, Jan Hendrik, Sabbadin, Marianna, Sumanasuriya, Semini, Crespo, Mateus, Sharp, Adam, Yuan, Wei, Grinu, Mathew, Boyle, Alexandra, Miller, Cynthia, Trotman, Lloyd, Delaleu, Nicolas, Fassan, Matteo, Moch, Holger, Viero, Gabriella, de Bono, Johann, Alimonti, Andrea (August 2023) The Akt/mTOR and MNK/eIF4E pathways rewire the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells. Nature Cancer, 4 (8). pp. 1102-1121. ISSN 2662-1347 (Public Dataset)

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Abstract

Cancer is highly infiltrated by myeloid-derived suppressor cells (MDSCs). Currently available immunotherapies do not completely eradicate MDSCs. Through a genome-wide analysis of the translatome of prostate cancers driven by different genetic alterations, we demonstrate that prostate cancer rewires its secretome at the translational level to recruit MDSCs. Among different secreted proteins released by prostate tumor cells, we identified Hgf, Spp1 and Bgn as the key factors that regulate MDSC migration. Mechanistically, we found that the coordinated loss of Pdcd4 and activation of the MNK/eIF4E pathways regulate the mRNAs translation of Hgf, Spp1 and Bgn. MDSC infiltration and tumor growth were dampened in prostate cancer treated with the MNK1/2 inhibitor eFT508 and/or the AKT inhibitor ipatasertib, either alone or in combination with a clinically available MDSC-targeting immunotherapy. This work provides a therapeutic strategy that combines translation inhibition with available immunotherapies to restore immune surveillance in prostate cancer.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression > phosphorylation diseases & disorders > cancer > cancer types > prostate cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > suppressor diseases & disorders > cancer > cancer types
CSHL Authors:	Trotman, Lloyd C. Mathew, Grinu Boyle, Alexandra Miller, Cynthia
Communities:	CSHL labs > Mills lab CSHL labs > Trotman lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	August 2023
Date Deposited:	21 Sep 2023 19:35
Last Modified:	08 Jan 2024 17:01
Related URLs:	Publisher
Dataset ID:	ArrayExpress: E-MTAB-9624 GEO: GSE202910 GEO: GSE202907
URI:	https://repository.cshl.edu/id/eprint/40957

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