- 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.
MetadatenAuthor: | Ann-Christin FrankORCiDGND, Rebecca Karin RaueGND, Dominik Christian FuhrmannORCiDGND, Evelyn Nicole Joy Sirait-FischerORCiDGND, Carsten ReuseGND, Andreas WeigertORCiDGND, Dieter LütjohannORCiD, Karsten HillerORCiDGND, Shahzad Nawaz SyedORCiDGND, Bernhard BrüneORCiD |
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URN: | urn:nbn:de:hebis:30:3-795613 |
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DOI: | https://doi.org/10.7150/thno.58380 |
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ISSN: | 1838-7640 |
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Parent Title (English): | Theranostics |
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Publisher: | Wyoming, NSW |
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Place of publication: | Ivyspring |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2021/06/04 |
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Date of first Publication: | 2021/06/04 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2023/11/28 |
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Tag: | Breast cancer; LDHB; RNA therapeutics; metabolism; tumor-associated macrophages |
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Volume: | 11 |
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Issue: | 15 |
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Page Number: | 19 |
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First Page: | 7570 |
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Last Page: | 7588 |
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Note: | The authors acknowledge the support of Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896. |
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Note: | Data availability
Ago-RIP-seq data are deposited in the ArrayExpress database at EMBL-EBI under the accession number E-MTAB-6943 [https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6943]. All relevant data are within the paper and its supplementary information files. Additional data that support the findings of this study are available from the corresponding authors upon reasonable request. |
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HeBIS-PPN: | 515678333 |
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Institutes: | Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - CC BY - Namensnennung 4.0 International |
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