Browsing by Author "Putluri, Nagireddy"

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    CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming
    (Wiley, 2021) Tao, Ling; Moreno-Smith, Myrthala; Ibarra-García-Padilla, Rodrigo; Milazzo, Giorgio; Drolet, Nathan A.; Hernandez, Blanca E.; Oh, Young S.; Patel, Ivanshi; Kim, Jean J.; Zorman, Barry; Patel, Tajhal; Kamal, Abu Hena Mostafa; Zhao, Yanling; Hicks, John; Vasudevan, Sanjeev A.; Putluri, Nagireddy; Coarfa, Cristian; Sumazin, Pavel; Perini, Giovanni; Parchem, Ronald J.; Uribe, Rosa A.; Barbieri, Eveline
    Neuroblastoma (NB) arises from oncogenic disruption of neural crest (NC) differentiation. Treatment with retinoic acid (RA) to induce differentiation has improved survival in some NB patients, but not all patients respond, and most NBs eventually develop resistance to RA. Loss of the chromatin modifier chromatin assembly factor 1 subunit p150 (CHAF1A) promotes NB cell differentiation; however, the mechanism by which CHAF1A drives NB oncogenesis has remained unexplored. This study shows that CHAF1A gain-of-function supports cell malignancy, blocks neuronal differentiation in three models (zebrafish NC, human NC, and human NB), and promotes NB oncogenesis. Mechanistically, CHAF1A upregulates polyamine metabolism, which blocks neuronal differentiation and promotes cell cycle progression. Targeting polyamine synthesis promotes NB differentiation and enhances the anti-tumor activity of RA. The authors' results provide insight into the mechanisms that drive NB oncogenesis and suggest a rapidly translatable therapeutic approach (DFMO plus RA) to enhance the clinical efficacy of differentiation therapy in NB patients.
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    Chronic exposure to carbon black ultrafine particles reprograms macrophage metabolism and accelerates lung cancer
    (AAAS, 2022) Chang, Cheng-Yen; You, Ran; Armstrong, Dominique; Bandi, Ashwini; Cheng, Yi-Ting; Burkhardt, Philip M.; Becerra-Dominguez, Luis; Madison, Matthew C.; Tung, Hui-Ying; Zeng, Zhimin; Wu, Yifan; Song, Lizhen; Phillips, Patricia E.; Porter, Paul; Knight, John M.; Putluri, Nagireddy; Yuan, Xiaoyi; Marcano, Daniela C.; McHugh, Emily A.; Tour, James M.; Catic, Andre; Maneix, Laure; Burt, Bryan M.; Lee, Hyun-Sung; Corry, David B.; Kheradmand, Farrah
    Chronic exposure to airborne carbon black ultrafine (nCB) particles generated from incomplete combustion of organic matter drives IL-17A–dependent emphysema. However, whether and how they alter the immune responses to lung cancer remains unknown. Here, we show that exposure to nCB particles increased PD-L1+ PD-L2+ CD206+ antigen-presenting cells (APCs), exhausted T cells, and Treg cells. Lung macrophages that harbored nCB particles showed selective mitochondrial structure damage and decreased oxidative respiration. Lung macrophages sustained the HIF1α axis that increased glycolysis and lactate production, culminating in an immunosuppressive microenvironment in multiple mouse models of non–small cell lung cancers. Adoptive transfer of lung APCs from nCB-exposed wild type to susceptible mice increased tumor incidence and caused early metastasis. Our findings show that nCB exposure metabolically rewires lung macrophages to promote immunosuppression and accelerates the development of lung cancer.
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    Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse
    (Public Library of Science, 2017) Wangler, Michael F.; Chao, Yu-Hsin; Bayat, Vafa; Giagtzoglou, Nikolaos; Shinde, Abhijit Babaji; Putluri, Nagireddy; Coarfa, Cristian; Donti, Taraka; Graham, Brett H.; Faust, Joseph E.; McNew, James A.; Moser, Ann; Sardiello, Marco; Baes, Myriam; Bellen, Hugo J.
    Peroxisome biogenesis disorders (PBD) are a group of multi-system human diseases due to mutations in the PEX genes that are responsible for peroxisome assembly and function. These disorders lead to global defects in peroxisomal function and result in severe brain, liver, bone and kidney disease. In order to study their pathogenesis we undertook a systematic genetic and biochemical study of Drosophila pex16 and pex2 mutants. These mutants are short-lived with defects in locomotion and activity. Moreover these mutants exhibit severe morphologic and functional peroxisomal defects. Using metabolomics we uncovered defects in multiple biochemical pathways including defects outside the canonical specialized lipid pathways performed by peroxisomal enzymes. These included unanticipated changes in metabolites in glycolysis, glycogen metabolism, and the pentose phosphate pathway, carbohydrate metabolic pathways that do not utilize known peroxisomal enzymes. In addition, mutant flies are starvation sensitive and are very sensitive to glucose deprivation exhibiting dramatic shortening of lifespan and hyperactivity on low-sugar food. We use bioinformatic transcriptional profiling to examine gene co-regulation between peroxisomal genes and other metabolic pathways and we observe that the expression of peroxisomal and carbohydrate pathway genes in flies and mouse are tightly correlated. Indeed key steps in carbohydrate metabolism were found to be strongly co-regulated with peroxisomal genes in flies and mice. Moreover mice lacking peroxisomes exhibit defective carbohydrate metabolism at the same key steps in carbohydrate breakdown. Our data indicate an unexpected link between these two metabolic processes and suggest metabolism of carbohydrates could be a new therapeutic target for patients with PBD.