The noradrenergic profile of plasma metanephrine in neuroblastoma patients is reproduced in xenograft mice models and arise from PNMT downregulation
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Karim Abid1, Maja Beck Popovic2, Katia Balmas Bourloud3, Jacqueline Schoumans4, Joana Grand-Guillaume1, Eric Grouzmann1 and Annick Mühlethaler-Mottet3
1 Catecholamine and Peptides Laboratory, Service of Clinical Pharmacology and Toxicology, Lausanne University Hospital and University of Lausanne, Switzerland
2 Pediatric Hematology-Oncology Unit, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Switzerland
3 Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Switzerland
4 Oncogenomics Laboratory, Hematology Service, Laboratory Medicine and Pathology Department, Lausanne University Hospital and University of Lausanne, Switzerland
|Annick Mühlethaler-Mottet,||email:||[email protected]|
|Karim Abid,||email:||[email protected]|
Keywords: neuroblastoma; metanephrine; patient-derived xenograft; mouse model; Phenylethanolamine N-Methyltransferase
Received: October 06, 2020 Accepted: December 16, 2020 Published: January 05, 2021
Metanephrines (MNs; normetanephrine (NMN), metanephrine (MN) and methoxytyramine (MT)) detected in urine or plasma represent the best biomarker for neuroblastoma (NB) diagnosis, however the metabolism of both catecholamine (CAT) and MNs remains enigmatic in NB. Using patient-derived xenograft (PDX) models derived from primary NB cells, we observed that the plasma levels of MNs in NB-PDX-bearing mice were comparable as in patients. Interestingly, murine plasma displayed an elevated fraction of glucuronidated forms of MNs relative to human plasma where sulfonated forms prevail. In tumors, the concentration ranges of MNs and CAT and the expression levels of the main genes involved in catecholamine metabolism were similar between NB-PDX and human NB tissues. Likewise, plasma and intratumoral profiles of individual MNs, with increased levels of MT and NMN relative to MN, were also conserved in mouse models as in patients. We further demonstrated the downregulation of the Phenylethanolamine N-Methyltransferase gene in NB biopsies and in NB-PDX explaining this biochemical phenotype, and giving a rational to the low levels of epinephrine and MN measured in NB affected patients. Thus, our subcutaneous murine NB-PDX models not only reproduce the phenotype of primary NB tumors, but also the metabolism of catecholamine as observed in patients. This may potentially open new avenues in preclinical studies for the follow up of novel therapeutic options for NB through the quantification of plasma MNs.
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