Rutgers Cancer Institute of New Jersey CINJ

Little Falls, NJ, United States

Rutgers Cancer Institute of New Jersey CINJ

Little Falls, NJ, United States
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Joshi S.,Rutgers Cancer Institute of New Jersey CINJ | Tolkunov D.,Rutgers Cancer Institute of New Jersey CINJ | Aviv H.,New Brunswick Laboratory | Hakimi A.A.,Sloan Kettering Cancer Center | And 5 more authors.
Cell Reports | Year: 2015

Oncocytomas are predominantly benign neoplasms possessing pathogenic mitochondrial mutations and accumulation of respiration-defective mitochondria, characteristics of unknown significance. Using exome and transcriptome sequencing, we identified two main subtypes of renal oncocytoma. Type 1 is diploid with CCND1 rearrangements, whereas type 2 is aneuploid with recurrent loss of chromosome 1, X or Y, and/or 14 and 21, which may proceed to more aggressive eosinophilic chromophobe renal cell carcinoma (ChRCC). Oncocytomas activate 5' adenosine monophosphate-activated protein kinase (AMPK) and Tp53 (p53) and display disruption of Golgi and autophagy/lysosome trafficking, events attributed to defective mitochondrial function. This suggests that the genetic defects in mitochondria activate a metabolic checkpoint, producing autophagy impairment and mitochondrial accumulation that limit tumor progression, revealing a novel tumor-suppressive mechanism for mitochondrial inhibition with metformin. Alleviation of this metabolic checkpoint in type 2 by p53 mutations may allow progression to eosinophilic ChRCC, indicating that they represent higher risk. Mechanisms that restrict tumors to benign disease inform approaches to cancer therapy. Joshi etal. report that genetic defects in mitochondrial respiration in benign oncocytomas block trafficking and activate p53, limiting tumor growth to benign disease. © 2015 The Authors.


Kumar N.,Rutgers University | Srivillibhuthur M.,Rutgers University | Joshi S.,Rutgers Cancer Institute of New Jersey CINJ | Walton K.D.,University of Michigan | And 10 more authors.
Development (Cambridge) | Year: 2016

During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders. © 2016. Published by The Company of Biologists Ltd.


White E.,Rutgers Cancer Institute of New Jersey CINJ | White E.,Rutgers University
Cold Spring Harbor Perspectives in Medicine | Year: 2016

Macroautophagy (autophagy hereafter) captures, degrades, and recycles intracellular components to maintain metabolic homeostasis and protein and organelle quality control. Autophagy thereby promotes survival in starvation and prevents tissue degeneration. There is an important relationship between autophagy and p53. Autophagy suppresses p53 and also p53 activates autophagy. The suppression of p53 by autophagy is important for tumor promotion and likely also for preventing tissue degeneration. Alternatively, the activation of autophagy by p53 suggests that autophagy is part of the protective function of p53. Uncovering the underlying mechanisms of the autophagy-p53 reciprocal functional interaction and has important implications for human disease and treatment. © 2016 Cold Spring Harbor Laboratory Press; All rights reserved.


White E.,Rutgers Cancer Institute of New Jersey CINJ | White E.,Rutgers University | Mehnert J.M.,Rutgers Cancer Institute of New Jersey CINJ | Mehnert J.M.,Rutgers University | And 2 more authors.
Clinical Cancer Research | Year: 2015

Macroautophagy (autophagy hereafter) captures intracellular proteins and organelles and degrades them in lysosomes. The degradation breakdown products are released from lysosomes and recycled into metabolic and biosynthetic pathways. Basal autophagy provides protein and organelle quality control by eliminating damaged cellular components. Starvation-induced autophagy recycles intracellular components into metabolic pathways to sustain mitochondrial metabolic function and energy homeostasis. Recycling by autophagy is essential for yeast and mammals to survive starvation through intracellular nutrient scavenging. Autophagy suppresses degenerative diseases and has a context-dependent role in cancer. In some models, cancer initiation is suppressed by autophagy. By preventing the toxic accumulation of damaged protein and organelles, particularly mitochondria, autophagy limits oxidative stress, chronic tissue damage, and oncogenic signaling, which suppresses cancer initiation. This suggests a role for autophagy stimulation in cancer prevention, although the role of autophagy in the suppression of human cancer is unclear. In contrast, some cancers induce autophagy and are dependent on autophagy for survival. Much in the way that autophagy promotes survival in starvation, cancers can use autophagy-mediated recycling to maintain mitochondrial function and energy homeostasis to meet the elevated metabolic demand of growth and proliferation. Thus, autophagy inhibition may be beneficial for cancer therapy. Moreover, tumors are more autophagy-dependent than normal tissues, suggesting that there is a therapeutic window. Despite these insights, many important unanswered questions remain about the exact mechanisms of autophagy-mediated cancer suppression and promotion, how relevant these observations are to humans, and whether the autophagy pathway can be modulated therapeutically in cancer. © 2015 American Association for Cancer Research.


PubMed | Cancer Research UK Research Institute, Rutgers Cancer Institute of New Jersey CINJ, Rutgers University and University of Michigan
Type: Journal Article | Journal: Development (Cambridge, England) | Year: 2016

During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders.

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