1/12 Check our latest work led by our Postdoc @fbonnay_vienna where we describe a fundamental role of mitochondrial fusion and oxidative metabolism for tumor cell immortalization, in the larval brain of #Drosophila melanogaster. sciencedirect.com/science/articl… 
2/12 Our tumor model of choice is derived from asymmetrically dividing neural stem cells (NSCs) called type II Neuroblasts, deficient for the tumor suppressor gene brain tumor or brat. brat-deficient type II Neuroblasts give rise to big and lethal brain tumors.
3/12 We first observed that brat tumors have increased oxidative metabolism compared to normal brains, with increased oxygen consumption and TriCarboxylic Acid (TCA) cycle metabolites.
4/12 In a very fruitful collaboration with @nervousfly lab, we showed by single-cell RNA-sequencing that the most proliferative tumor cells also have the strongest oxidative metabolism signature while the least proliferative cells have a stronger glycolytic signature.
5/12 We then demonstrate that oxygen-dependent metabolism is required for tumor growth, either by reducing enzymes of the TCA cycle or the Electron Transport Chain (ETC), or by manipulating oxygen concentrations.
6/12 Interestingly, ETC complex II and flavoproteins were not required for brat tumorigenesis, suggesting a specific function of aerobic metabolism independent of FAD/FADH2 metabolism in this process.
7/12 Mitochondrial fusion-mediating enzymes marf (Drosophila MFN2) and opa-1 were increased in tumor cells compared to normal NSCs and tumor cells showed elongated, fused mitochondria. RNAi of either marf or opa-1 prevented tumor-specific oxidative metabolism and tumor growth.
8/12 Using an NAD+/NADH fluorescent sensor and mitochondrial markers, we temporally mapped this metabolic shift during tumor initiation: 48h-old tumor initiating cells had fused #mitochondria and strikingly high levels of NAD+ and NADH.
9/12In brat depleted type II NB lineages, 48h are required for quiescent tumor initiating cells to start dividing and irreversibly convert into immortal tumor cells. Blocking oxidative metabolism or mitochondrial fusion prevented brat tumor initiating cells to start proliferation
10/12Finally, we could rescue tumor formation of ATPase-deficient brat tumor cells by over-expressing the yeast proton-pump-independent NADH dehydrogenase Ndi1, further suggesting a key role of NAD+/NADH metabolism for the immortalization of these oxidative tumor initiating cells
11/12 Our work highlights once more that #metabolism and #mitochondrial dynamics can play instructive roles during cell fate determination, and calls for deeper investigations on the function of oxidative metabolism during #tumorigenesis in mammals.
12/12 A big thank you to all contributors of this work, among which are our two alumni @abdusselamoglu and @lisa_landskron !
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