Characterization and metabolic synthetic lethal testing in a new model of SDH-loss familial pheochromocytoma and paraganglioma

John Smestad, Oksana Hamidi, Lin Wang, Molly Nelson Holte, Fatimah Al Khazal, Luke Erber, Yue Chen, L. James Maher

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Succinate dehydrogenase (SDH)-loss pheochromocytoma and paraganglioma (PPGL) are tumors driven by metabolic derangement. SDH loss leads to accumulation of intracellular succinate, which competitively inhibits dioxygenase enzymes, causing activation of pseudohypoxic signaling and hypermethylation of histones and DNA. The mechanisms by which these alterations lead to tumorigenesis are unclear, however. In an effort to fundamentally understand how SDH loss reprograms cell biology, we developed an immortalized mouse embryonic fibroblast cell line with conditional disruption of Sdhc and characterize the kinetics of Sdhc gene rearrangement, SDHC protein loss, succinate accumulation, and the resultant hypoproliferative phenotype. We further perform global transcriptomic, epigenomic, and proteomic characterization of changes resulting from SDHC loss, identifying specific perturbations at each biological level. We compare the observed patterns of epigenomic derangement to another previously-described immortalized mouse chromaffin cell model of SDHB loss, and compare both models to human SDH-loss tumors. Finally, we perform analysis of SDHC synthetic lethality with lactate dehydrogenase A (LDHA) and pyruvate carboxylase (PCX), which are important for regeneration of NAD+ and aspartate biosynthesis, respectively. Our data show that SDH-loss cells are selectively vulnerable to LDH genetic knock-down or chemical inhibition, suggesting that LDH inhibition may be an effective therapeutic strategy for SDH-loss PPGL.

Original languageEnglish (US)
Pages (from-to)6109-6127
Number of pages19
JournalOncotarget
Volume9
Issue number5
DOIs
StatePublished - 2018

Bibliographical note

Funding Information:
4R01CA166025-04 and 4T32GM065841-14 and the Paradifference Foundation. JS is supported by 1F30 CA220660-01 and the Mayo Clinic Medical Scientist Training Program. LW was supported by the Mayo Clinic Graduate School of Biomedical Sciences.

Funding Information:
This work was made possible by the Mayo Clinic Metabolomics Resource Core (NIH grant U24DK100469), Mayo Clinic Medical Genome Facility Sequencing Core, and the Mayo Clinic Research Computing FacilityThis work was supported by NIH grants 4R01CA166025-04 and 4T32GM065841-14 and the Paradifference Foundation. JS is supported by 1F30 CA220660-01 and the Mayo Clinic Medical Scientist Training Program. LW was supported by the Mayo Clinic Graduate School of Biomedical Sciences.

Funding Information:
This work was made possible by the Mayo Clinic Metabolomics Resource Core (NIH grant U24DK100469),

Publisher Copyright:
© Smestad et al.

Keywords

  • Epigenomics, proteomics
  • Lactate dehydrogenase
  • Synthetic lethality
  • Transcriptomics

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