Melanoma brain metastasis is independent of lactate dehydrogenase A expression.

Abstract

BACKGROUND:

The key metabolic enzyme lactate dehydrogenase A (LDHA) is overexpressed in many cancers, and several preclinical studies have shown encouraging results of targeted inhibition. However, the mechanistic importance of LDHA in melanoma is largely unknown and hitherto unexplored in brain metastasis.

METHODS:

We investigated the spatial, temporal, and functional features of LDHA expression in melanoma brain metastasis across multiple in vitro assays, in a robust and predictive animal model employing MRI and PET imaging, and in a unique cohort of 80 operated patients. We further assessed the genomic and proteomic landscapes of LDHA in different cancers, particularly melanomas.

RESULTS:

LDHA expression was especially strong in early and small brain metastases in vivo and related to intratumoral hypoxia in late and large brain metastases in vivo and in patients. However, LDHA expression in human brain metastases was not associated with the number of tumors, BRAF(V600E) status, or survival. Moreover, LDHA depletion by small hairpin RNA interference did not affect cell proliferation or 3D tumorsphere growth in vitro or brain metastasis formation or survival in vivo. Integrated analyses of the genomic and proteomic landscapes of LDHA indicated that LDHA is present but not imperative for tumor progression within the CNS, or predictive of survival in melanoma patients.

CONCLUSIONS:

In a large patient cohort and in a robust animal model, we show that although LDHA expression varies biphasically during melanoma brain metastasis formation, tumor progression and survival seem to be functionally independent of LDHA.

• Authors: Terje Sundstrøm, Heidi Espedal, Patrick N Harter, Kristine Eldevik Fasmer, Kai Ove Skaftnesmo, Sindre Horn, Erlend Hodneland, Michel Mittelbronn, Benjamin Weide, Rudi Beschorner, Benjamin Bender, Cecilie Brekke Rygh, Morten Lund-Johansen, Rolf Bjerkvig, Frits Thorsen
• Journal: Neuro-oncology (Neuro Oncol) Vol. 17 Issue 10 Pg. 1374-85 (Oct 2015) ISSN: 1523-5866 [Electronic] England
• PMID: 25791837 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Isoenzymes
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5

Topics

• Animals
• Brain Neoplasms (metabolism, secondary)
• Cell Hypoxia
• Cell Line, Tumor
• Female
• Gene Knockdown Techniques
• Humans
• Isoenzymes (genetics, metabolism)
• L-Lactate Dehydrogenase (genetics, metabolism)
• Lactate Dehydrogenase 5
• Melanoma (pathology)
• Mice
• Survival Analysis