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

by Crespo, Mateus , Mirenda, Michela , Trotman, Lloyd , Guccini, Ilaria , D’Ambrosio, Mariantonietta , Lauria, Fabio , Fassan, Matteo , Colucci, Manuel , Valdata, Aurora , Sharp, Adam , Alimonti, Andrea , Bolis, Marco , Sabbadin, Marianna , Grinu, Mathew , Parhizgari, Nahjme , Mosole, Simone , Alajati, Abdullah , Troiani, Martina , Moch, Holger , Revandkar, Ajinkya , Delaleu, Nicolas , Maddalena, Martino , Yuan, Wei , Miller, Cynthia , Barry, Simon , de Bono, Johann , Calì, Bianca , Rinaldi, Andrea , Brina, Daniela , Pasquini, Emiliano , Attanasio, Giuseppe , Tebaldi, Toma , Viero, Gabriella , Ponzoni, Adele , Calcinotto, Arianna , Sumanasuriya, Semini , Donzel, Deborah , Rüschoff, Jan Hendrik , Boyle, Alexandra

in Biglycan - metabolism / Couples / Eukaryotic Initiation Factor-4E - genetics / Eukaryotic Initiation Factor-4E - metabolism / Genomes / Hepatocyte Growth Factor - metabolism / Humans / Kinases / Ligands / Male / Myeloid Cells - metabolism / Osteopontin - metabolism / Phosphorylation / Prostate cancer / Prostatic Neoplasms - genetics / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Protein synthesis / Proteins / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Recruitment / Ribonucleic acid / RNA / TOR Serine-Threonine Kinases - metabolism / Tumors

2023

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

2023

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2023

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Journal Article

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

Crespo, Mateus,

Mirenda, Michela,

Trotman, Lloyd,

Guccini, Ilaria,

D’Ambrosio, Mariantonietta,

Lauria, Fabio,

Fassan, Matteo,

Colucci, Manuel,

Valdata, Aurora,

Sharp, Adam,

Alimonti, Andrea,

Bolis, Marco,

Sabbadin, Marianna,

Grinu, Mathew,

Parhizgari, Nahjme,

Mosole, Simone,

Alajati, Abdullah,

Troiani, Martina,

Moch, Holger,

Revandkar, Ajinkya,

Delaleu, Nicolas,

Maddalena, Martino,

Yuan, Wei,

Miller, Cynthia,

Barry, Simon,

de Bono, Johann,

Calì, Bianca,

Rinaldi, Andrea,

Brina, Daniela,

Pasquini, Emiliano,

Attanasio, Giuseppe,

Tebaldi, Toma,

Viero, Gabriella,

Ponzoni, Adele,

Calcinotto, Arianna,

Sumanasuriya, Semini,

Donzel, Deborah,

Rüschoff, Jan Hendrik,

Boyle, Alexandra

2023

Overview

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.

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Publisher

Nature Publishing Group

Subject

Biglycan - metabolism

/ Couples

/ Eukaryotic Initiation Factor-4E - genetics

/ Eukaryotic Initiation Factor-4E - metabolism

/ Genomes

/ Hepatocyte Growth Factor - metabolism

/ Humans