Browsing by Author "Zhao, Hongyun"

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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; Bioengineering; Chemical and Biomolecular Engineering
    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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    Tumor Microenvironment Derived Exosomes Pleiotropically Modulate Cancer Cell Metabolism
    (2016-12-01) Zhao, Hongyun; Nagrath, Deepak
    Exosomes are extracellular vesicles responsible for efficient cell-to-cell communications. We intended to investigate the role of tumor microenvironment (TME) derived exosomes in regulating cancer cell metabolism. We found that the isolated exosomes from cancer-associated fibroblasts (CAFs), a major cellular type in TME were uptaken by cancer cells efficiently. Viability assays proved that CAF-derived exosomes (CDEs) enhanced cancer cells viability in nutrient deprived medium to a large extent. In the followed metabolic tests, we found that CDEs downregulate mitochondrial function in both prostate and pancreatic cancer cells, which causes compensatory upregulation of glycolysis in these cells. We found that the possible mechanism of this metabolic regulation is through transfer of miRNAs by CDEs into the cancer cells. We showed that miRNAs contained in CDEs induced mitochondrial dysfunction. Considering that cancer cells in vivo reside in a nutrient-deprived microenvironment of nutrients deprivation and cancer cells’ avid growth needs huge amounts of nutrients, we proposed that CDEs were able to supply nutrients such as lipids, TCA cycle metabolites and amino acids to cancer cells. To prove this, we cultured cancer cells in nutrients deprived medium which is deprived of glutamine, pyruvate, lysine, phenylalanine, and leucine. CDEs were added to the medium to prove that CDEs can maintain cancer cells growth in nutrient deprived conditions similar to complete medium. Surprisingly, the CDEs added to the nutrient-deprived medium endowed cancer cells ability to maintain growth similar to complete medium. The direct rationale to explain it is that CDEs transferred nutrients to and were being utilized by cancer cells. The high throughput metabolomics methods showed that CDEs contained lipids, TCA cycle metabolites, and amino acids. Our results convincingly demonstrate that not only do exosomes enhance the phenomenon of “Warburg effect” in tumors, but remarkably, contain de novo “off-the-shelf” metabolites within their cargo that can contribute to the entire compendia of central carbon metabolism within cancer cells. Disruption of this CDEs-induced metabolic adaptation in cancer cells might provide a novel therapeutic avenue for exploitation.
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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; Bioengineering; Chemical and Biomolecular Engineering; 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.