Charting the cross-functional map between transcription factors and cancer metabolism

Transcriptional reprogramming of cellular metabolism is a hallmark feature of cancer. However, a systematic approach to study the role of transcription factors (TFs) in mediating cancer metabolic rewiring is missing. Here, we chart a genome-scale map of TF-metabolite associations in human using a new combined computational-experimental framework for large-scale metabolic profiling of adherent cell lines, and the integration of newly generated intracellular metabolic profiles of 54 cancer cell lines with transcriptomic and proteomic data. We unravel a large space of dependencies between TFs and central metabolic pathways, suggesting that the regulation of carbon metabolism in tumors may be more diverse and flexible than previously appreciated. This map provides an unprecedented resource to predict TFs responsible for metabolic transformation in patient-derived tumor samples, opening new opportunities in designing modulators of oncogenic TFs and in understanding disease etiology.