期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 7, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI148667
关键词
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资金
- Spanish Ministry of Science and Innovation-ISCIII [PI15/00623, PI18/00458, PI21/01208, CP18/00076, FI19/00193]
- European Regional Development (FEDER)
- Basque Department of Health [2017111011]
- Fun-dacion SEOM (Beca SEOM-Font Vella)
- Fundacion Gangoiti
- Ikerbasque Basque Research Foundation
- Basque Govern-ment Doctoral Training Grants
- AECC PhD Fellowship
- Career Development Fellow-ship from the Cancer Institute New South Wales [2019/CDF002]
- European Research Council (ERC) [ERC-2018-StG 804236-NEXTGEN-IO]
- Spanish Min-istry of Science and Innovation [PID2019-107956RA-I00, RYC2018-024183-I]
- Basque Department of Industry, Tourism and Trade (Elkartek)
- MICINN [PID2019-108787RB-I00, SAF2016-81975-REDT]
- European Training Networks Project [H2020-MSCA-ITN-308 2016 721532]
- AECC [GCT-RA18006CARR]
- Vencer el Cancer Foundation
- La Caixa Founda-tion [100010434]
- ERC [819242]
- FEDER funds
- ISCIII
- Cancer Council NSW project grant [RG18-03]
- Nation-al Breast Cancer Foundation Elaine Henry Fellowship [IIRS-21-096]
- Institute of Cancer Research, Span-ish Ministry of Science and Innovation [RYC-2016-20352, RTI2018-096778-A-I00]
- Asociacion Espanola Contra el Cancer [LABAE19044CALV]
- BBVA Leonardo Awards [IN [19] _BBM_BAS_0076]
- European Research Council (ERC) [819242] Funding Source: European Research Council (ERC)
This study reveals the pivotal role of the cytokine oncostatin M (OSM) in regulating interactions between immune and nonimmune stromal cells and epithelial cancer cells. It demonstrates that the stromal OSM/OSMR axis reprograms the tumor microenvironment and plays a key role in breast cancer progression.
The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.
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