Mapping Spatial Energy Metabolism in Tumors Using MALDI Imaging Mass Spectrometry

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Abstract:

Tumors have altered metabolism, in particular high glycolytic flux (Warburg metabolism). Altered tumor metabolism can be used to enable tumor identification and is also correlated with tumor progression and metastasis. However, it is not known whether metabolism varies spatially within tumors, and whether such variation affects tumor growth. We developed an approach to measure glycolysis flux with high spatial resolution (down to 10 μm2) by combining IV infusion of 2-deoxyglucose with MALDI imaging mass spectrometry of mouse tumors. We found that pancreatic tumors exhibit glycolysis-high and -low zones, with a four-fold difference in glycolysis flux between regions. In contrast, the other energy-producing pathway, the TCA cycle, was uniform across the tumor. We found that glycolysis flux was upregulated in poorly perfused tumor regions. Acute treatment with a KRAS inhibitor, recently approved to treat pancreatic cancer, strongly reduced tumor glycolysis in most but not all tumor cells. In future, we will test whether cells with high glycolysis in the presence of drug give rise to drug resistance. Overall, we present a platform to combine tracer infusion and MALDI imaging mass spectrometry to measure spatial metabolism in tissues and tumors.