Browsing by Author "Ram, Prahlad T."
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Item Mapping Network Motif Tunability and Robustness in the Design of Synthetic Signaling Circuits(Public Library of Science, 2014) Iadevaia, Sergio; Nakhleh, Luay K.; Azencott, Robert; Ram, Prahlad T.Cellular networks are highly dynamic in their function, yet evolutionarily conserved in their core network motifs or topologies. Understanding functional tunability and robustness of network motifs to small perturbations in function and structure is vital to our ability to synthesize controllable circuits. In establishing core sets of network motifs, we selected topologies that are overrepresented in mammalian networks, including the linear, feedback, feed-forward, and bifan circuits. Static and dynamic tunability of network motifs were defined as the motif ability to respectively attain steady-state or transient outputs in response to pre-defined input stimuli. Detailed computational analysis suggested that static tunability is insensitive to the circuit topology, since all of the motifs displayed similar ability to attain predefined steady state outputs in response to constant inputs. Dynamic tunability, in contrast, was tightly dependent on circuit topology, with some motifs performing superiorly in achieving observed time-course outputs. Finally, we mapped dynamic tenability onto motif topologies to determine robustness of motif structures to changes in topology and identify design principles for the rational assembly of robust synthetic networks.Item Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer(EMBO, 2014) Yang, Lifeng; Moss, Tyler; Mangala, Lingegowda S.; Marini, Juan; Zhao, Hongyun; Wahlig, Stephen; Armaiz-Pena, Guillermo; Jiang, Dahai; Achreja, Abhinav; Win, Julia; Roopaimoole, Rajesha; Rodriguez-Aguayo, Cristian; Mercado-Uribe, Imelda; Lopez-Berestein, Gabriel; Liu, Jinsong; Tsukamoto, Takashi; Sood, Anil K.; Ram, Prahlad T.; Nagrath, DeepakGlutamine can play a critical role in cellular growth in multiple cancers. Glutamine‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.Item Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism(eLife Sciences Publications Ltd., 2016) Zhao, Hongyun; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Bernard, Vincent; Moss, Tyler; Marini, Juan C.; Tudawe, Thavisha; Seviour, Elena G.; San Lucas, F. Anthony; Alvarez, Hector; Gupta, Sonal; Maiti, Sourindra N.; Cooper, Laurence; Peehl, Donna; Ram, Prahlad T.; Maitra, Anirban; Nagrath, Deepak; Laboratory for Systems Biology of Human DiseasesCancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.