Browsing by Author "Achreja, Abhinav"

Now showing 1 - 5 of 5
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    Amplification of USP13 drives ovarian cancer metabolism
    (Springer Nature, 2016) Han, Cecil; Yang, Lifeng; Choi, Hyun Ho; Baddour, Joelle; Achreja, Abhinav; Liu, Yunhua; Li, Yujing; Li, Jiada; Wan, Guohui; Huang, Cheng; Ji, Guang; Zhang, Xinna; Nagrath, Deepak; Lu, Xiongbin
    Dysregulated energetic metabolism has been recently identified as a hallmark of cancer. Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer. More often, cancer metabolism is re-engineered by altered abundance and activity of the metabolic enzymes. Here we identify ubiquitin-specific peptidase 13 (USP13) as a master regulator that drives ovarian cancer metabolism. USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis. The USP13 gene is co-amplified with PIK3CA in 29.3% of high-grade serous ovarian cancers and its overexpression is significantly associated with poor clinical outcome. Inhibiting USP13 remarkably suppresses ovarian tumour progression and sensitizes tumour cells to the treatment of PI3K/AKT inhibitor. Our results reveal an important metabolism-centric role of USP13, which may lead to potential therapeutics targeting USP13 in ovarian cancers.
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    Mapping tumor metabolism: from personalized multiobjective metabolic flux analysis to intercellular metabolite transport via exosomes
    (2016-12-02) Achreja, Abhinav; Nagrath, Deepak
    Departure from healthy and tightly-regulated metabolism is an emerging hallmark of cancer that facilitates tumorigenic characteristics of uncontrolled proliferation, metastasis, and resistance to chemotherapy. Our aim is to elucidate underlying mechanisms of metabolic shifts that satisfy enhanced energetic and biochemical demands of cancer cells. This is essential to develop therapies that sensitize resistant tumors to front-line treatments and alleviate side-effects or attack novel targets that are robust to acquired resistance. Study of metabolic reprogramming involves a marriage of empirical techniques that measure biophysical parameters and computational algorithms to estimate useful but unmeasurable parameters of metabolic activity, i.e. fluxes. This thesis describes novel computational algorithms designed to quantify metabolic fluxes vis a vis metabolic reprogramming in cancer cells and metabolic interaction within tumor microenvironment (TME). The first part describes reconstruction of metabolic models using transcriptomic and proteomic data from cancer cell-lines to address the need for personalized medicine. The second part discusses the implementation of currently used 13-carbon metabolic flux analysis (13C-MFA) to demonstrate how cancer-associated fibroblasts (CAFs) in TME, reprogram metabolism to utilize nutrients atypically, to synthesize glutamine for glutamine deprived cancer cells. In the third part, the 13C multiobjective MFA (13C-MOMFA) algorithm is presented that removes the restrictions of 13C-MFA to simple models and abundant empirical data. The empirical data utilized is same as conventional techniques, but with a multiobjective optimization approach to capture competing metabolic objectives facilitating various tumorigenic functions in larger “personalized” models. 13C-MOMFA is applied in ovarian cancer cell-lines subjected to glutamine catabolism inhibition, to uncover mechanisms linking invasiveness to glutamine-dependence. Finally, exosome-mediated MFA (Exo-MFA) technique is designed to elucidate tumor growth-supporting transport of metabolites from tumor stroma to nutrient-deprived cancer cells via secreted exosomes. Exo-MFA is the first to capture multicellular metabolic interaction between TME components. Results demonstrate packaging of nutrients into exosomes by CAFs, and sufficient supply of metabolites to central carbon metabolism of nutrient-deprived cancer cells. This thesis addresses two burgeoning fields of cancer biology focused on improving therapeutic outcomes – (i) precision medicine that recognizes patient-heterogeneity and complex metabolic programs that support tumorigenic phenotypes, and (ii) systems approach to understanding metabolism of whole tumors.
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    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, Deepak
    Glutamine 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.
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    Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma
    (Springer Nature, 2017) Ju, Huai-Qiang; Ying, Haoqiang; Tian, Tian; Ling, Jianhua; Fu, Jie; Lu, Yu; Wu, Min; Yang, Lifeng; Achreja, Abhinav; Chen, Gang; Zhuang, Zhuonan; Wang, Huamin; Nagrath, Deepak; Yao, Jun; Hung, Mien-Chie; DePinho, Ronald A.; Huang, Peng; Xu, Rui-Hua; Chiao, Paul J.; Laboratory for Systems Biology of Human Diseases
    Kras activation and p16 inactivation are required to develop pancreatic ductal adenocarcinoma (PDAC). However, the biochemical mechanisms underlying these double alterations remain unclear. Here we discover that NAD(P)H oxidase 4 (NOX4), an enzyme known to catalyse the oxidation of NAD(P)H, is upregulated when p16 is inactivated by looking at gene expression profiling studies. Activation of NOX4 requires catalytic subunit p22phox, which is upregulated following Kras activation. Both alterations are also detectable in PDAC cell lines and patient specimens. Furthermore, we show that elevated NOX4 activity accelerates oxidation of NADH and supports increased glycolysis by generating NAD+, a substrate for GAPDH-mediated glycolytic reaction, promoting PDAC cell growth. Mechanistically, NOX4 was induced through p16-Rb-regulated E2F and p22phox was induced by KrasG12V-activated NF-κB. In conclusion, we provide a biochemical explanation for the cooperation between p16 inactivation and Kras activation in PDAC development and suggest that NOX4 is a potential therapeutic target for PDAC.
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    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 Diseases
    Cancer-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.