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

被引：35

作者：

Brina, Daniela ^{[1
]}

Ponzoni, Adele ^{[1
,19
]}

Troiani, Martina ^{[1
,2
]}

Cali, Bianca ^{[1
]}

Pasquini, Emiliano ^{[1
]}

Attanasio, Giuseppe ^{[1
]}

Mosole, Simone ^{[1
]}

Mirenda, Michela ^{[1
,20
]}

D'Ambrosio, Mariantonietta ^{[1
,21
]}

Colucci, Manuel ^{[1
]}

Guccini, Ilaria ^{[1
,22
]}

Revandkar, Ajinkya ^{[1
,23
]}

Alajati, Abdullah ^{[1
,24
]}

Tebaldi, Toma ^{[3
,4
]}

Donzel, Deborah ^{[5
]}

Lauria, Fabio ^{[5
]}

Parhizgari, Nahjme ^{[1
,25
]}

Valdata, Aurora ^{[1
]}

Maddalena, Martino ^{[1
]}

Calcinotto, Arianna ^{[1
]}

Bolis, Marco ^{[2
,6
,7
]}

Rinaldi, Andrea ^{[1
]}

Barry, Simon ^{[8
]}

Rueschoff, Jan Hendrik ^{[9
]}

Sabbadin, Marianna ^{[10
]}

Sumanasuriya, Semini ^{[11
,12
]}

Crespo, Mateus ^{[11
,12
]}

Sharp, Adam ^{[11
,12
]}

Yuan, Wei ^{[11
,12
]}

Grinu, Mathew ^{[13
]}

Boyle, Alexandra ^{[13
]}

Miller, Cynthia ^{[13
]}

Trotman, Lloyd ^{[13
]}

Delaleu, Nicolas ^{[14
]}

Fassan, Matteo ^{[10
,15
]}

Moch, Holger ^{[9
]}

Viero, Gabriella ^{[5
]}

de Bono, Johann ^{[11
,12
,16
]}

Alimonti, Andrea ^{[1
,2
,17
,18
]}

机构：

[1] Oncol Inst Southern Switzerland, Inst Oncol Res, Bellinzona, Switzerland

[2] Univ Svizzera Italiana, Fac Biomed Sci, Lugano, Switzerland

[3] Yale Univ, Dept Internal Med, Sch Med, New Haven, CT USA

[4] Yale Canc Ctr, New Haven, CT USA

[5] CNR Unit Trento, Inst Biophys, Povo, Italy

[6] Swiss Inst Bioinformat, Bioinformat Core Unit, Bellinzona, Switzerland

[7] Ist Ric Farmacol Mario Negri IRCCS, Dept Oncol, Computat Oncol Unit, Milan, Italy

[8] Li Ka Shing Ctr, IMED Oncol AstraZeneca, Cambridge, England

[9] Univ Hosp Zurich USZ, Dept Pathol & Mol Pathol, Zurich, Switzerland

[10] Veneto Inst Oncol, IOV IRCCS, Padua, Italy

[11] Royal Marsden NHS Fdn Trust, London, England

[12] Inst Canc Res, London, England

[13] Cold Spring Harbor Lab, New York, NY USA

[14] TI, 2cSysBioMed, Contra, Switzerland

[15] Univ Padua, Dept Med DIMED, Surg Pathol Unit, Padua, Italy

[16] Royal Marsden Hosp, London, England

[17] Univ Padua, Venetian Inst Mol Med, Dept Med, Padua, Italy

[18] Eidgenoss TH ETH Zurich, Dept Hlth Sci & Technol, Zurich, Switzerland

[19] Ima Biotech, Lille, France

[20] Evotec, Toulouse, France

[21] Imperial Coll London, London, England

[22] Swiss Fed Inst Technol, Inst Mol Hlth Sci, Zurich, Switzerland

[23] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Boston, MA USA

[24] Univ Klinikum Bonn, Dept Urol, Bonn, Germany

[25] Biosun Pharmed, Kordan, Iran

来源：

NATURE CANCER | 2023年 / 4卷 / 08期

关键词：

LYMPHOCYTE RATIO; DOUBLE-BLIND; PTEN; CHEMOTHERAPY; INITIATION; SENESCENCE; PDCD4; PHOSPHORYLATION; TUMORIGENESIS; DEGRADATION;

D O I：

10.1038/s43018-023-00594-z

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. Alimonti and colleagues show that coordinated activation of the Akt/mTOR and MNK/eIF4E pathways rewires the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells, which can be therapeutically targeted.

引用

页码：1102 / +

页数：43

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