TY  - JOUR
A1  - Frank, Ann-Christin
A1  - Raue, Rebecca Karin
A1  - Fuhrmann, Dominik Christian
A1  - Sirait-Fischer, Evelyn Nicole Joy
A1  - Reuse, Carsten
A1  - Weigert, Andreas
A1  - Lütjohann, Dieter
A1  - Hiller, Karsten
A1  - Syed, Shahzad Nawaz
A1  - Brüne, Bernhard
T1  - Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment
T2  - Theranostics
N2  - 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.
KW  - Breast cancer
KW  - LDHB
KW  - RNA therapeutics
KW  - metabolism
KW  - tumor-associated macrophages
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/79561
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-795613
SN  - 1838-7640
N1  - The authors acknowledge the support of Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896.
N1  - 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.
VL  - 11
IS  - 15
SP  - 7570
EP  - 7588
PB  - Wyoming, NSW
CY  - Ivyspring
ER  -