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dc.contributor.authorFrank, Ann-Christin
dc.contributor.authorRaue, Rebecca
dc.contributor.authorFuhrmann, Dominik C
dc.contributor.authorSirait-Fischer, Evelyn
dc.contributor.authorReuse, Carsten
dc.contributor.authorWeigert, Andreas
dc.contributor.authorLütjohann, Dieter
dc.contributor.authorHiller, Karsten
dc.contributor.authorSyed, Shahzad Nawaz
dc.contributor.authorBrüne, Bernhard
dc.date.accessioned2021-07-22T13:37:31Z
dc.date.available2021-07-22T13:37:31Z
dc.date.issued2021-06-04
dc.identifier.citationTheranostics. 2021 Jun 4;11(15):7570-7588. doi: 10.7150/thno.58380.en_US
dc.identifier.pmid34158867
dc.identifier.doi10.7150/thno.58380
dc.identifier.urihttp://hdl.handle.net/10033/622952
dc.description.abstractBackground: Glucose metabolism in the tumor-microenvironment is a fundamental hallmark for tumor growth and intervention therein remains an attractive option for anti-tumor therapy. Whether tumor-derived factors such as microRNAs (miRs) regulate glucose metabolism in stromal cells, especially in tumor-associated macrophages (TAMs), to hijack them for trophic support, remains elusive. Methods: Ago-RIP-Seq identified macrophage lactate dehydrogenase B (LDHB) as a target of tumor-derived miR-375 in both 2D/3D cocultures and in murine TAMs from a xenograft mouse model. The prognostic value was analyzed by ISH and multiplex IHC of breast cancer patient tissues. Functional consequences of the miR-375-LDHB axis in TAMs were investigated upon mimic/antagomir treatment by live metabolic flux assays, GC/MS, qPCR, Western blot, lentiviral knockdown and FACS. The therapeutic potential of a combinatorial miR-375-decoy/simvastatin treatment was validated by live cell imaging. Results: Macrophage LDHB decreased in murine and human breast carcinoma. LDHB downregulation increase aerobic glycolysis and lactagenesis in TAMs in response to tumor-derived miR-375. Lactagenesis reduced fatty acid synthesis but activated SREBP2, which enhanced cholesterol biosynthesis in macrophages. LDHB downregulation skewed TAMs to function as a lactate and sterol/oxysterol source for the proliferation of tumor cells. Restoring of LDHB expression potentiated inhibitory effects of simvastatin on tumor cell proliferation. Conclusion: Our findings identified a crucial role of LDHB in macrophages and established tumor-derived miR-375 as a novel regulator of macrophage metabolism in breast cancer, which might pave the way for strategies of combinatorial cancer cell/stroma cell interventions.en_US
dc.language.isoenen_US
dc.publisherIvyspring International publisheren_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectBreast canceren_US
dc.subjectLDHBen_US
dc.subjectRNA therapeuticsen_US
dc.subjectmetabolismen_US
dc.subjecttumor-associated macrophages.en_US
dc.titleLactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment.en_US
dc.typeArticleen_US
dc.identifier.eissn1838-7640
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalTheranosticsen_US
dc.source.volume11
dc.source.issue15
dc.source.beginpage7570
dc.source.endpage7588
refterms.dateFOA2021-07-22T13:37:32Z
dc.source.journaltitleTheranostics
dc.source.countryAustralia


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International