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Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment.
Frank, Ann-Christin Raue, Rebecca Fuhrmann, Dominik C Sirait-Fischer, Evelyn Reuse, Carsten Weigert, Andreas Lütjohann, Dieter Hiller, Karsten Syed, Shahzad Nawaz Brüne, Bernhard
Frank, Ann-Christin
Raue, Rebecca
Fuhrmann, Dominik C
Sirait-Fischer, Evelyn
Reuse, Carsten
Weigert, Andreas
Lütjohann, Dieter
Hiller, Karsten
Syed, Shahzad Nawaz
Brüne, Bernhard
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2021-06-04
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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.
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Theranostics. 2021 Jun 4;11(15):7570-7588. doi: 10.7150/thno.58380.
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en
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1838-7640
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Attribution 4.0 International