Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage.

Deng, Haibin; Gao, Yanyun; Trappetti, Verdiana; Hertig, Damian; Karatkevich, Darya; Losmanová, Tereza; Urzì, Christian; Ge, Huixiang; Geest, Gerrit Adriaan; Bruggmann, Remy; Djonov, Valentin; Nuoffer, Jean-Marc; Vermathen, Peter; Zamboni, Nicola; Riether, Carsten; Ochsenbein, Adrian; Peng, Ren-Wang; Kocher, Gregor Jan; Schmid, Ralph; Dorn, Patrick; ... (2022). Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage. Cellular and molecular life sciences, 79(8), p. 445. SP Birkhäuser Verlag Basel 10.1007/s00018-022-04453-5

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Once considered a waste product of anaerobic cellular metabolism, lactate has been identified as a critical regulator of tumorigenesis, maintenance, and progression. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in regulating metabolism during tumorigenesis is largely unknown. To determine whether LDHB plays a pivotal role in tumorigenesis, we performed 2D and 3D in vitro experiments, utilized a conventional xenograft tumor model, and developed a novel genetically engineered mouse model (GEMM) of non-small cell lung cancer (NSCLC), in which we combined an LDHB deletion allele with an inducible model of lung adenocarcinoma driven by the concomitant loss of p53 (also known as Trp53) and expression of oncogenic KRAS (G12D) (KP). Here, we show that epithelial-like, tumor-initiating NSCLC cells feature oxidative phosphorylation (OXPHOS) phenotype that is regulated by LDHB-mediated lactate metabolism. We show that silencing of LDHB induces persistent mitochondrial DNA damage, decreases mitochondrial respiratory complex activity and OXPHOS, resulting in reduced levels of mitochondria-dependent metabolites, e.g., TCA intermediates, amino acids, and nucleotides. Inhibition of LDHB dramatically reduced the survival of tumor-initiating cells and sphere formation in vitro, which can be partially restored by nucleotide supplementation. In addition, LDHB silencing reduced tumor initiation and growth of xenograft tumors. Furthermore, we report for the first time that homozygous deletion of LDHB significantly reduced lung tumorigenesis upon the concomitant loss of Tp53 and expression of oncogenic KRAS without considerably affecting the animal's health status, thereby identifying LDHB as a potential target for NSCLC therapy. In conclusion, our study shows for the first time that LDHB is essential for the maintenance of mitochondrial metabolism, especially nucleotide metabolism, demonstrating that LDHB is crucial for the survival and proliferation of NSCLC tumor-initiating cells and tumorigenesis.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Institute of Diagnostic, Interventional and Paediatric Radiology > DCR Magnetic Resonance Spectroscopy and Methodology (AMSM)
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Faculty Institutions > Teaching Staff, Faculty of Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Endocrinology/Metabolic Disorders
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Deng, Haibin; Gao, Yanyun; Trappetti, Verdiana; Hertig, Damian; Karatkevich, Darya; Losmanová, Tereza; Urzì, Christian; Ge, Huixiang; van Geest, Gerrit Adriaan; Bruggmann, Rémy; Djonov, Valentin Georgiev; Nuoffer, Jean-Marc; Riether, Carsten; Ochsenbein, Adrian; Peng, Ren-Wang; Kocher, Gregor; Schmid, Ralph; Dorn, Patrick and Marti, Thomas

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1420-682X

Publisher:

SP Birkhäuser Verlag Basel

Language:

English

Submitter:

Anette van Dorland

Date Deposited:

27 Jul 2022 09:13

Last Modified:

20 Sep 2022 15:53

Publisher DOI:

10.1007/s00018-022-04453-5

PubMed ID:

35877003

Uncontrolled Keywords:

Cancer stem cells Cellular plasticity Lung cancer Mitochondrial DNA Mitochondrial metabolism Nucleotide metabolism Tumorigenicity

BORIS DOI:

10.48350/171528

URI:

https://boris.unibe.ch/id/eprint/171528

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