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

Male Humans Protein Serine-Threonine Kinases / genetics Proto-Oncogene Proteins c-akt / genetics Phosphorylation Eukaryotic Initiation Factor-4E / genetics TOR Serine-Threonine Kinases / metabolism Prostatic Neoplasms / genetics Myeloid Cells / metabolism Hepatocyte Growth Factor / metabolism Osteopontin / metabolism Biglycan / metabolism

Journal

Nature cancer

ISSN: 2662-1347

Titre abrégé: Nat Cancer

Pays: England

ID NLM: 101761119

Informations de publication

Date de publication:
08 2023

Historique:

received: 09 05 2022

accepted: 13 06 2023

medline: 25 8 2023

pubmed: 18 7 2023

entrez: 17 7 2023

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s43018-023-00594-z PMID: 37460872

pubmed: 37460872

doi: 10.1038/s43018-023-00594-z

pii: 10.1038/s43018-023-00594-z

doi:

Substances chimiques

Protein Serine-Threonine Kinases EC 2.7.11.1

Proto-Oncogene Proteins c-akt EC 2.7.11.1

Eukaryotic Initiation Factor-4E 0

TOR Serine-Threonine Kinases EC 2.7.11.1

HGF protein, human 0

Hepatocyte Growth Factor 67256-21-7

SPP1 protein, human 0

Osteopontin 106441-73-0

BGN protein, human 0

Biglycan 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1102-1121

Informations de copyright

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