Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment

  • 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.

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Author: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
Parent Title (English):Theranostics
Publisher:Wyoming, NSW
Place of publication:Ivyspring
Document Type:Article
Date of Publication (online):2021/06/04
Date of first Publication:2021/06/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/11/28
Tag:Breast cancer; LDHB; RNA therapeutics; metabolism; tumor-associated macrophages
Page Number:19
First Page:7570
Last Page:7588
The authors acknowledge the support of Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896.
Data availability

Ago-RIP-seq data are deposited in the ArrayExpress database at EMBL-EBI under the accession number 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.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International