The Akt/mTOR and MNK/eIF4E Pathways Rewire the Prostate Cancer Translatome to Secrete HGF, SPP1 and BGN and Recruit Suppressive Myeloid Cells

Overview

Journal Nat Cancer

Specialty Oncology

Date 2023 Jul 17

PMID 37460872

Authors

Daniela Brina

Adele Ponzoni

Martina Troiani

Bianca Cali

Emiliano Pasquini

Giuseppe Attanasio

Simone Mosole

Michela Mirenda

Mariantonietta DAmbrosio

Manuel Colucci

Ilaria Guccini

Ajinkya Revandkar

Abdullah Alajati

Toma Tebaldi

Deborah Donzel

Fabio Lauria

Nahjme Parhizgari

Aurora Valdata

Martino Maddalena

Arianna Calcinotto

Marco Bolis

Andrea Rinaldi

Simon Barry

Jan Hendrik Ruschoff

Marianna Sabbadin

Semini Sumanasuriya

Mateus Crespo

Adam Sharp

Wei Yuan

Mathew Grinu

Alexandra Boyle

Cynthia Miller

Lloyd Trotman

Nicolas Delaleu

Matteo Fassan

Holger Moch

Gabriella Viero

Johann de Bono

Andrea Alimonti

Affiliations

Soon will be listed here.

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.

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