Biology subjects

Eisenhofer, G.

Publications and source records attributed to Eisenhofer, G..

4 recordsLinked to original sources

bioRxiv2025

Patient-derived organoids reveal hypoxia-driven plasticity and therapeutic vulnerabilities in pheochromocytomas and paragangliomas

Pheochromocytomas and paragangliomas (PPGLs) are rare chromaffin cell-derived neuroendocrine tumors of sympathetic (catecholamine-producing) or parasympathetic (nonsecretory) origin, frequently driven by dysregulation of hypoxia-inducible factor (HIF) signaling, particularly HIF-2. Although often benign, PPGLs can metastasize unpredictably, with limited therapeutic options once disseminated. Progress has been hindered by the lack of robust preclinical models, especially those that capture their molecular complexity and microenvironmental influences. To address this gap, we established patient-derived tumor organoids (PDOs) from 35 PPGLs, encompassing a broad spectrum of clinical and molecular phenotypes. The organoids retained key immunohistochemical, genomic, transcriptomic, and catecholamine-secretory features of their parental tumors. PPGL organoids cultured under hypoxic conditions generally exhibited enhanced viability, supporting hypoxia as a driver of cell survival. Hypoxia activated HIF-1 and expanded ASCL1+ cell populations, suggesting a lineage shift toward an immature chromaffin state. In contrast, long-term normoxic cultures activated hypoxia inducible factor 2 (HIF-2) and acquired a hybrid sympathoblast-mesenchymal identity in subpopulations with upregulation of extracellular matrix and cell cycle markers, independent of genotype. These features resemble high-risk neuroblastoma subtypes and establish a molecular parallel suggestive of shared lineage plasticity and pathogenic programs, detectable in primary PPGLs. Drug screening across a library of up to 51 drugs and combinations revealed both shared and unique vulnerabilities, with response rates to approved therapies matching clinical observations. The CDK4/6 inhibitor abemaciclib, previously unexplored in PPGLs, elicited the strongest activity. Abemaciclib-responsive PDOs and their matched tumors, including a metastatic sample, exhibited epithelial mesenchyme transition enrichment, nominating potential biomarkers for patient stratification. Our results establish PDOs as a novel platform for modeling neuroendocrine tumor biology, reveal microenvironment-driven plasticity in PPGLs, with potential translational relevance, and identify actionable vulnerabilities in a disease with few effective systemic therapies. Main findingsO_LIPDOs can be successfully generated from PPGLs of various genetic backgrounds and reflect parental tumor properties C_LIO_LIPDO cultures grown in hypoxia retain main molecular features of parental tumors, have increased viability and a more immature developmental/biosynthetic profile C_LIO_LILong term PDOs grown for 4 weeks in normoxia activate HIF2, drift toward a hybrid sympathoblast-mesenchymal-like identity resembling relapsed/therapy resistant neuroblastomas, features that can be detected in primary tumors C_LIO_LIA subset of PDOs respond to Abemaciclib, a drug class not previously used therapeutically in PPGLs C_LI

cancer biology↗

bioRxiv2021

GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy

Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Here, we found that radioresistant PCa cells and prostate cancer stem cells (CSCs) have a high glutamine demand. Glutaminase (GLS)-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as glutaminase (GLS) and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populations in vivo and reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.

cancer biology↗

bioRxiv2020

Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland

The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signalling on its function remains scarcely understood. Here, we reveal that deficiency of HIF (Hypoxia Inducible Factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis. Concomitant loss of PHD2 in renal erythropoietin (EPO) producing cells stimulated HIF2-driven EPO overproduction, excessive RBC formation (erythrocytosis) and systemic hypoglycaemia. Using mouse lines displaying only EPO-induced erythrocytosis or anaemia, we show that hypo- or hyperglycaemia is necessary and sufficient to respectively enhance or reduce exocytosis of epinephrine from the adrenal gland. Based on these results, we propose that the PHD2-HIF2 axis in the adrenal medulla and beyond regulates both synthesis and release of catecholamines, especially epinephrine. Our findings are also of great significance in view of the small molecule PHD inhibitors being tested in phase III global clinical development trials for use in renal anaemia patients.

molecular biology↗

bioRxiv2017

Compensation For Chronic Oxidative Stress In ALADIN Null Mice

BackgroundMutations in the AAAS gene coding for the nuclear pore complex protein ALADIN lead to the autosomal recessive disorder triple A syndrome. Triple A patients present with a characteristic phenotype including alacrima, achalasia and adrenal insufficiency. Patient fibroblasts show increased levels of oxidative stress and several in vitro studies demonstrated that the nucleoporin ALADIN is involved in the cellular oxidative stress response and in adrenal steroidogenesis. We showed that ALADIN knock-out mice lack a phenotype resembling human triple A syndrome. Thus, we hypothesized that application of chronic oxidative stress by ingestion of paraquat will generate triple A-like phenotype in ALADIN null mice.\n\nResultsWe demonstrate that ALADIN knock-out mice present with an unexpected compensated glutathione metabolism still lacking a phenotype resembling human triple A syndrome after application of chronic oxidative stress. We could not observe increased levels of oxidative stress and alterations in adrenal steroidogenesis in mice depleted for ALADIN.\n\nConclusionsThis study stresses the species-specific role of the nucleoporin ALADIN presenting a novel compensatory mechanism of the cellular glutathione redox response and shedding light on the role of ALADIN in the cell.

cell biology↗