ECE2022 Poster Presentations Pituitary and Neuroendocrinology (127 abstracts)
Targeting invasive pituitary adenomas: in vitro studies and in vivo investigations in a murine model of invasive pituitary tumors obtained by orthotopic pituitary GC cells injection
Fanny Chasseloup 1 , Etienne Lefevre 1 , Alexandre Dormoy 1 , Nataly Ladurelle 1 , Tiphaine Mignot 1 , Clément Janot 1 , Mirella Hage 1 , Say Viengchareun 1 , Philippe Zizzari 2 , Philippe Chanson 1,3 , Michael Buchfelder 4 & Peter Kamenicky 1,3
1Université Paris-Saclay, INSERM U1185 << Physiologie et Physiopathologie Endocriniennes >>, France; 2Université de Bordeaux, INSERM U1215, Neurocentre Magendie, France; 3AP-HP, Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l’Hypophyse, France; 4Universitätsklinikum Erlangen, Department of Neurosurgery, Germany
Context: Surgical removal is the primary treatment option for pituitary adenomas. However, pituitary surgery is frequently incomplete because of invasion of extrasellar cerebral structures, notably, of the cavernous sinus. Our objective was to study the molecular basis of the cavernous sinus invasion by pituitary adenomas.
Methods: We analyzed a tissue collection of 19 invasive pituitary adenomas with a sample from the intrasellar portion and a sample from the portion invading the cavernous sinus of each adenoma. We used RNA-sequencing to compare gene expression patterns of the invading and intrasellar portions. The implication of one differentially expressed candidate gene in the invasive behavior was first analyzed in vitro in lactosomatotroph GH3 and gonadotroph LbT2 cells. We used Transwell Assay to analyze the impact of pharmacologic inhibition of the candidate gene on cell migration and invasion. To study the role of this gene on tumor growth and behavior in vivo, we elaborated a model of invasive pituitary adenomas by stereotactic injection of murine somatotroph GC cells into the pituitary gland of female Wistar Furth rats. Twelve adult rats received 20.000 GC cells in each pituitary lobe. Tumor development was assessed fortnightly by 7Tesla MRI. Six of the 12 rats were treated with the pharmacological inhibitor of the candidate gene. Rats were sacrificed 7 weeks after cell injection.
Results: RNA-sequencing identified 159 up-regulated genes and 11 down-regulated genes in the invasive adenoma portions. In vitro pharmacological inhibition of the selected candidate gene decreased cell migration and invasion in GH3 cells (P=0.0205 andP=0.0038) and LbT2 cell (P=0.0345 andP=0.0131). Amongst the 12 injected rats, 11 (92%) developed invasive pituitary tumors. Tumor growth was rapid, causing death from intracranial hypertensions before the end of the protocol in 7 animals. Pharmacological inhibition tended to slow tumor growth from 30.3 mm3 /week to 7.8 mm3 /week (P=0.12) and decreased cumulative mortality (83% in untreated animals vs 33% in treated animals, P=0.08).
Conclusion: We described the molecular signature associated with the invasive behavior of pituitary adenomas and identified a therapeutic target, which is related to pituitary cells migration and invasion in functional in vitrostudies. Pharmacologic inhibition of this target tended to decrease tumor growth and mortality in vivo, however larger numbers of animals are necessary to confirm this pilot observation. Our original approach of orthotopic cell injection into rat pituitaries resulting in tumor development provides a new tool for molecular studies of pituitary tumorigenesis and for pharmacological screening.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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