Pheochromocytoma/paraganglioma preclinical models: which to use and why?

Martinelli, Serena; Maggi, Mario; Rapizzi, Elena

doi:10.1530/ec-20-0472

Cited by 10 publications

(9 citation statements)

References 57 publications

(67 reference statements)

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“…Pseudohypoxic PPGLs are more prone to develop metastatic disease [5], but available in vitro models often lack typical characteristics of a pseudohypoxic phenotype, such as an immature catecholamine phenotype, increased pro-metastatic behavior, and upregulation of hypoxia-related genes under normoxic conditions [11]. Based on the hypothesis that recurrent cycles of extrinsic hypoxia (≤1% oxygen) leads to a manifestation of a pseudohypoxic phenotype, we established PC12 sub-cell lines using repeated exposure to hypoxia-reoxygenation cycles.…”

Section: Recurrent Cycles Of Hypoxia Lead To the Establishment Of A P...mentioning

confidence: 99%

“…This provides a rational for targeting HIF2α and DNA methylation in metastatic PPGLs, particularly for those with mutations in SDHB. Currently available preclinical in vitro models to evaluate such novel therapeutic approaches present with different limitations and often lack characteristic features of aggressive cluster 1 PPGLs [11,12]. Moreover, genetically engineered cell lines only reflect the changes associated with the particular mutation and do not allow for general conclusions about the increased aggressiveness of cluster 1 tumors and the associated therapeutic response.…”

Section: Introductionmentioning

confidence: 99%

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Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model

Helm

Drukewitz

Poser

et al. 2022

Cells

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Continuous activation of hypoxia pathways in pheochromocytomas and paragangliomas (PPGLs) is associated with higher disease aggressiveness, for which effective treatment strategies are still missing. Most of the commonly used in vitro models lack characteristics of these pseudohypoxic tumors, including elevated expression of hypoxia-inducible factor (HIF) 2α. To address this shortcoming, we investigated whether recurrent hypoxia cycles lead to continuous activation of hypoxia pathways under normoxic conditions and whether this pseudohypoxia is associated with increased cellular aggressiveness. Rat pheochromocytoma cells (PC12) were incubated under hypoxia for 24 h every 3–4 days, up to 20 hypoxia–reoxygenation cycles, resulting in PC12 Z20 cells. PC12 Z20 control cells were obtained by synchronous cultivation under normoxia. RNA sequencing revealed upregulation of HIF2α in PC12 Z20 cells and a pseudohypoxic gene signature that overlapped with the gene signature of pseudohypoxic PPGLs. PC12 Z20 cells showed a higher growth rate, and the migration and adhesion capacity were significantly increased compared with control cells. Changes in global methylation, together with the pseudohypoxic conditions, may be responsible for the increased aggressiveness of this new model. The established sub-cell line with characteristics of pseudohypoxic PPGLs represent a complementary model for further investigations, for example, with regard to new therapeutic approaches.

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Section: Recurrent Cycles Of Hypoxia Lead To the Establishment Of A P...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model

Helm

Drukewitz

Poser

et al. 2022

Cells

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“…In fact, they can be easily standardized, and yet, they provide enough complexity, such as 3D geometry, to represent relevant aspects of human tumours [ 38 ]. Spheroids generation facilitates the growth of highly uniform spheroids and allow real-time monitoring of drug-induced changes in their phenotypes [ 27 , 39 , 40 ]. We previously demonstrated that TME, represented by primary CAFs, plays a fundamental and specific role in inducing the invasion properties of spheroid cells and that this effect is extraordinarily enhanced in MTT SDHB sil ones [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Martinelli

Amore

Mello

et al. 2022

Cancers

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Pheochromocytoma/paragangliomas (PPGLs) are neuroendocrine tumours, often non-metastatic, but without available effective treatment for their metastatic form. Recent studies have shown that metformin exhibits antiproliferative activity in many human cancers, including PPGLs. Nevertheless, no data are available on the role of metformin on PPGL cells (two-dimension, 2D) and spheroids (three-dimension, 3D) migration/invasion. In this study, we observed that metformin exerts an antiproliferative effect on 2D and 3D cultures of pheochromocytoma mouse tumour tissue (MTT), either silenced or not for the SDHB subunit. However, metformin did not affect MTT migration. On the other hand, metformin did not have a short-term effect on the proliferation of mouse primary fibroblasts, but significantly decreased their ability to migrate. Although the metabolic changes induced by metformin were similar between MTT and fibroblasts (i.e., an overall decrease of ATP production and an increase in intracellular lactate concentration) the activated signalling pathways were different. Indeed, after metformin administration, MTT showed a reduced phosphorylation of Akt and Erk1/2, while fibroblasts exhibited a downregulation of N-Cadherin and an upregulation of E-Cadherin. Herein, we demonstrated that metformin has different effects on cell growth and spread depending on the cell type nature, underlining the importance of the tumour microenvironment in dictating the drug response.

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“…It will be of major interest for future studies to evaluate discrepancies between the models in more detail, also with respect to dysfunction of other SDH subunits. However, to date no comparable models with knockout of the different subunits is available (56).…”

Section: Discussionmentioning

confidence: 99%

Succinate Mediates Tumorigenic Effects via Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas

et al. 2021

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Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D (SDHx) mutations. SDHx mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 (SUCNR1) in SDHB PPGLs and SDHD head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to SDHx mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of SDHx mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in SDHx PPGLs and after SDHB knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of SUCNR1-transfected PC12 and ERK pathway signaling compared to control cells. Candidate SUCNR1 inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in SDHx PPGLs, providing a growth advantage via SUCNR1.

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Pheochromocytoma/paraganglioma preclinical models: which to use and why?

Cited by 10 publications

References 57 publications

Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model

Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Succinate Mediates Tumorigenic Effects via Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas

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