Publications by authors named "Judith Goncalves"

7 Publications

  • Page 1 of 1

Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate.

Cancer Res 2021 Jul 14;81(13):3480-3494. Epub 2021 Jun 14.

PARCC, INSERM UMR970, Equipe Labellisée par la Ligue Contre le Cancer, Paris, France.

Succinate dehydrogenase is a key enzyme in the tricarboxylic acid cycle and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, but only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an knockout chromaffin cell line and compared it with deficient cells. Both cell types exhibited similar SDH loss of function, metabolic adaptation, and succinate accumulation. In contrast, cells showed hallmarks of mesenchymal transition associated with increased DNA hypermethylation and a stronger pseudo-hypoxic phenotype compared with cells. Loss of SDHB specifically led to increased oxidative stress associated with dysregulated iron and copper homeostasis in the absence of NRF2 activation. High-dose ascorbate exacerbated the increase in mitochondrial reactive oxygen species, leading to cell death in cells. These data establish a mechanism linking oxidative stress to iron homeostasis that specifically occurs in -deficient cells and may promote metastasis. They also highlight high-dose ascorbate as a promising therapeutic strategy for SDHB-related cancers. SIGNIFICANCE: Loss of different succinate dehydrogenase subunits can lead to different cell and tumor phenotypes, linking stronger 2-OG-dependent dioxygenases inhibition, iron overload, and ROS accumulation following SDHB mutation.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2936DOI Listing
July 2021

An update on adult forms of hereditary pheochromocytomas and paragangliomas.

Curr Opin Oncol 2021 01;33(1):23-32

Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.

Purpose Of Review: Pheochromocytomas and paragangliomas (PPGL) display a strong genetic determinism with 40% of inherited forms. The purpose of this review is to provide an update on current knowledge on adult forms of hereditary PPGL and their management.

Recent Findings: PPGL are genetically-driven in 70% of cases, with germline and/or somatic mutations identified in more than 20 genes. Although eight new susceptibility genes have recently emerged, mutations on SDHx genes remain the most frequent. In addition to SDHB, mutations in SLC25A11, FH and MDH2 may predispose to a metastatic disease and somatic alterations including TERT and ATRX mutations, and the differential expression on noncoding RNAs are also associated with the occurrence of metastases.The biochemical diagnosis remains the mainstay of functional PPGL and does not differ between hereditary PPGL while the choice of the best nuclear imaging approach is dictated by the tumor type and can be influenced by the presence of a germline mutation (18F-DOPA PET/CT for cluster 2 mutation and Ga-DOTATATE PET/CT for cluster 1 mutation).

Summary: A systematic genetic testing and counselling is recommended for all PPGL patients and should lead to conservative surgery and an adapted follow up, in case of hereditary form.
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http://dx.doi.org/10.1097/CCO.0000000000000694DOI Listing
January 2021

TET-Mediated Hypermethylation Primes SDH-Deficient Cells for HIF2α-Driven Mesenchymal Transition.

Cell Rep 2020 03;30(13):4551-4566.e7

Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, 75015 Paris, France. Electronic address:

Loss-of-function mutations in the SDHB subunit of succinate dehydrogenase predispose patients to aggressive tumors characterized by pseudohypoxic and hypermethylator phenotypes. The mechanisms leading to DNA hypermethylation and its contribution to SDH-deficient cancers remain undemonstrated. We examine the genome-wide distribution of 5-methylcytosine and 5-hydroxymethylcytosine and their correlation with RNA expression in SDHB-deficient tumors and murine Sdhb cells. We report that DNA hypermethylation results from TET inhibition. Although it preferentially affects PRC2 targets and known developmental genes, PRC2 activity does not contribute to the DNA hypermethylator phenotype. We also prove, in vitro and in vivo, that TET silencing, although recapitulating the methylation profile of Sdhb cells, is not sufficient to drive their EMT-like phenotype, which requires additional HIF2α activation. Altogether, our findings reveal synergistic roles of TET repression and pseudohypoxia in the acquisition of metastatic traits, providing a rationale for targeting HIF2α and DNA methylation in SDH-associated malignancies.
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http://dx.doi.org/10.1016/j.celrep.2020.03.022DOI Listing
March 2020

Succinate dehydrogenase deficiency in a chromaffin cell model retains metabolic fitness through the maintenance of mitochondrial NADH oxidoreductase function.

FASEB J 2020 01 22;34(1):303-315. Epub 2019 Nov 22.

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Mutations in succinate dehydrogenase (SDH) lead to the development of tumors in a restricted subset of cell types, including chromaffin cells and paraganglia. The molecular basis for this specificity is currently unknown. We show that loss of SDH activity in a chromaffin cell model does not perturb complex I function, retaining the ability to oxidize NADH within the electron transport chain. This activity supports continued oxidation of substrates within the tricarboxylic acid (TCA) cycle. However, due to the block in the TCA cycle at SDH, the high glutamine oxidation activity is only maintained through an efflux of succinate. We also show that although the mitochondria of SDH-deficient cells are less active per se, their higher mass per cell results in an overall respiratory rate that is comparable with wild-type cells. Finally, we observed that when their mitochondria are uncoupled, SDH-deficient cells are unable to preserve their viability, suggesting that the mitochondrial metabolic network is unable to compensate when exposed to additional stress. We therefore show that in contrast to models of SDH deficiency based on epithelial cells, a chromaffin cell model retains aspects of metabolic "health," which could form the basis of cell specificity of this rare tumor type.
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http://dx.doi.org/10.1096/fj.201901456RDOI Listing
January 2020

Synergistic Highly Potent Targeted Drug Combinations in Different Pheochromocytoma Models Including Human Tumor Cultures.

Endocrinology 2019 11;160(11):2600-2617

Medizinische Klinik und Poliklinik IV, Klinikum der Universität, LMU München, Munich, Germany.

There are no officially approved therapies for metastatic pheochromocytomas apart from ultratrace 131I-metaiodbenzylguanidine therapy, which is approved only in the United States. We have, therefore, investigated the antitumor potential of molecular-targeted approaches in murine pheochromocytoma cell lines [monocyte chemoattractant protein (MPC)/monocyte chemoattractant protein/3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], immortalized mouse chromaffin Sdhb-/- cells, three-dimensional pheochromocytoma tumor models (MPC/MTT spheroids), and human pheochromocytoma primary cultures. We identified the specific phosphatidylinositol-3-kinase α inhibitor BYL719 and the mammalian target of rapamycin inhibitor everolimus as the most effective combination in all models. Single treatment with clinically relevant doses of BYL719 and everolimus significantly decreased MPC/MTT and Sdhb-/- cell viability. A targeted combination of both inhibitors synergistically reduced MPC and Sdhb-/- cell viability and showed an additive effect on MTT cells. In MPC/MTT spheroids, treatment with clinically relevant doses of BYL719 alone or in combination with everolimus was highly effective, leading to a significant shrinkage or even a complete collapse of the spheroids. We confirmed the synergism of clinically relevant doses of BYL719 plus everolimus in human pheochromocytoma primary cultures of individual patient tumors with BYL719 attenuating everolimus-induced AKT activation. We have thus established a method to assess molecular-targeted therapies in human pheochromocytoma cultures and identified a highly effective combination therapy. Our data pave the way to customized combination therapy to target individual patient tumors.
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http://dx.doi.org/10.1210/en.2019-00410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795182PMC
November 2019

Emerging molecular markers of metastatic pheochromocytomas and paragangliomas.

Ann Endocrinol (Paris) 2019 Jun 11;80(3):159-162. Epub 2019 Apr 11.

Inserm, UMR970, équipe labellisée Ligue Contre le Cancer, Paris-Cardiovascular Research Center, 75015 Paris, France; Faculté de médecine, PRES Sorbonne Paris-Cité, Paris-Descartes University, 75006 Paris, France. Electronic address:

Metastatic pheochromocytoma/paraganglioma (PPGL) represents a major clinical challenge due to limitations in accurate diagnostic tools and effective treatments. Currently, patients classified at high-risk by means of clinical, biochemical and genetic criteria, require a lifelong monitoring, while it remains difficult to determine the metastatic potential of PPGL only on the basis of histopathological features. Thus, tumor molecular markers that improve the risk stratification of these patients are needed. In the past few years, we have witnessed an unprecedented molecular characterization of PPGL, which led to the emergence of promising candidate biomarkers predictive of metastatic behavior. Here, we briefly discuss these breakthroughs and provide some insights for the prospective implementation of molecular markers of metastatic PPGL in the clinical setting in years to come.
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http://dx.doi.org/10.1016/j.ando.2019.04.003DOI Listing
June 2019

Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis.

Cell Tissue Res 2018 05 9;372(2):379-392. Epub 2018 Feb 9.

INSERM UMR970, Paris-Cardiovascular Research Center, Equipe Labellisée Ligue Contre le Cancer, 56 rue Leblanc, F-75015, Paris, France.

Paragangliomas and pheochromocytomas are rare neuroendocrine tumors characterized by a large spectrum of hereditary predisposition. Based on gene expression profiling classification, they can be classically assigned to either a hypoxic/angiogenic cluster (cluster 1 including tumors with mutations in SDHx, VHL and FH genes) or a kinase-signaling cluster (cluster 2 consisting in tumors related to RET, NF1, TMEM127 and MAX genes mutations, as well as most of the sporadic tumors). The past 15 years have seen the emergence of an increasing number of genetically engineered and grafted models to investigate tumorigenesis and develop new therapeutic strategies. Among them, only cluster 2-related predisposed models have been successful but grafted models are however available to study cluster 1-related tumors. In this review, we present an overview of existing rodent models targeting predisposition genes involved or not in human pheochromocytoma/paraganglioma susceptibility and their contribution to the improvement of pheochromocytoma experimental research.
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http://dx.doi.org/10.1007/s00441-018-2797-yDOI Listing
May 2018
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