Germline BAP1 mutations induce a Warburg effect

Abstract

Carriers of heterozygous germline BAP1 mutations (BAP1+/−) develop cancer. We studied plasma from 16 BAP1+/− individuals from 2 families carrying different germline BAP1 mutations and 30 BAP1 wild-type (BAP1WT) controls from these same families. Plasma samples were analyzed by liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS), ultra-performance liquid chromatography triple quadrupole mass spectrometry (UPLC-TQ-MS), and gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found a clear separation in the metabolic profile between BAP1WT and BAP1+/− individuals. We confirmed the specificity of the data in vitro using 12 cell cultures of primary fibroblasts we derived from skin punch biopsies from 12/46 of these same individuals, 6 BAP1+/− carriers and 6 controls from both families. BAP1+/− fibroblasts displayed increased aerobic glycolysis and lactate secretion, and reduced mitochondrial respiration and ATP production compared with BAP1WT. siRNA-mediated downregulation of BAP1 in primary BAP1WT fibroblasts and in primary human mesothelial cells, led to the same reduced mitochondrial respiration and increased aerobic glycolysis as we detected in primary fibroblasts from carriers of BAP1+/− mutations. The plasma and cell culture results were highly reproducible and were specifically and only linked to BAP1 status and not to gender, age or family, or cell type, and required an intact BAP1 catalytic activity. Accordingly, we were able to build a metabolomic model capable of predicting BAP1 status with 100% accuracy using data from human plasma. Our data provide the first experimental evidence supporting the hypothesis that aerobic glycolysis, also known as the ‘Warburg effect’, does not necessarily occur as an adaptive process that is consequence of carcinogenesis, but rather that it may also predate malignancy by many years and facilitate carcinogenesis.

Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma

“…Recent experiments, however, showed a novel BAP1 cytoplasmic activity: wt BAP1 localizes at the endoplasmic reticulum, and has a role in promoting apoptosis via Ca2+ mitochondrial changes . Moreover, it was shown that cells from individuals carrying heterozygous germline BAP1 mutations have a distinctive metabolic signature, consisting in impairment of mitochondrial respiration and increase of aerobic glycolysis leading to a Warburg effect . Metastatic potential and prognosis in UM lacking BAP1 functions could be influenced also by these mechanisms, Warburg effect creating an environment that promotes tumor growth in hypoxia, and impaired apoptosis increasing the resistance to chemotherapy‐induced apoptosis.…”

Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine

“…Therefore, cells from BAP1 mutation carriers do not need to go through a selection process that favours the emergence of clones with a Warburg effect required for tumor growth: BAP1 +/− cells constitutionally derive a large part of their metabolism through aerobic glycolysis. Thus when these cells develop mutations they are already primed for cancer growth [158].…”

Tumor suppressive Ca2+ signaling is driven by IP3 receptor fitness

“…Germline mutations in BAP1 greatly enhanced the sensitivity of mice to develop mesothelioma when exposed to asbestos [50]. Recently, it has been shown in patient fibroblasts that loss of BAP1 displayed a metabolic rewiring towards aerobic glycolysis and reduced mitochondrial respiration associated with malignancy and carcinogenesis [51]. BAP1 was therefore identified as a novel IP 3 R3-interacting protein that impacts its post-translational modification.…”