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Intracarotid Cancer Cell Injection to Produce Mouse Models of Brain Metastasis
Published on: February 8, 2017
Melanoma brain metastasis is independent of lactate dehydrogenase A expression
Terje Sundstrøm1, Heidi Espedal1, Patrick N Harter1
1Department of Biomedicine, University of Bergen, Bergen, Norway (T.S., H.E., K.O.S., S.H., E.H., C.B.R., R.Bj., F.T.); Department of Clinical Medicine, University of Bergen, Bergen, Norway (T.S., M.L.-J.); Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway (T.S., M.L.-J.); Edinger-Institute (Neurological Institute), Goethe-University Medical School, Frankfurt am Main, Germany (P.N.H., M.M.); Center for Nuclear Medicine/PET, Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway (K.E.F.); Department of Dermatology, University Medical Center, Tübingen, Germany (B.W.); Department of Immunology, University of Tübingen, Tübingen, Germany (B.W.); Department of Neuropathology, Institute for Pathology and Neuropathology, University of Tübingen, Tübingen, Germany (R.Be.); Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany (B.B.); NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg (R.Bj.).
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.
