Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment.
dc.contributor.author | Frank, Ann-Christin | |
dc.contributor.author | Raue, Rebecca | |
dc.contributor.author | Fuhrmann, Dominik C | |
dc.contributor.author | Sirait-Fischer, Evelyn | |
dc.contributor.author | Reuse, Carsten | |
dc.contributor.author | Weigert, Andreas | |
dc.contributor.author | Lütjohann, Dieter | |
dc.contributor.author | Hiller, Karsten | |
dc.contributor.author | Syed, Shahzad Nawaz | |
dc.contributor.author | Brüne, Bernhard | |
dc.date.accessioned | 2021-07-22T13:37:31Z | |
dc.date.available | 2021-07-22T13:37:31Z | |
dc.date.issued | 2021-06-04 | |
dc.identifier.citation | Theranostics. 2021 Jun 4;11(15):7570-7588. doi: 10.7150/thno.58380. | en_US |
dc.identifier.pmid | 34158867 | |
dc.identifier.doi | 10.7150/thno.58380 | |
dc.identifier.uri | http://hdl.handle.net/10033/622952 | |
dc.description.abstract | Background: 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.iso | en | en_US |
dc.publisher | Ivyspring International publisher | en_US |
dc.rights | Attribution 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | Breast cancer | en_US |
dc.subject | LDHB | en_US |
dc.subject | RNA therapeutics | en_US |
dc.subject | metabolism | en_US |
dc.subject | tumor-associated macrophages. | en_US |
dc.title | Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment. | en_US |
dc.type | Article | en_US |
dc.identifier.eissn | 1838-7640 | |
dc.contributor.department | HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. | en_US |
dc.identifier.journal | Theranostics | en_US |
dc.source.volume | 11 | |
dc.source.issue | 15 | |
dc.source.beginpage | 7570 | |
dc.source.endpage | 7588 | |
refterms.dateFOA | 2021-07-22T13:37:32Z | |
dc.source.journaltitle | Theranostics | |
dc.source.country | Australia |