Preclinical transgenic and patient‐derived xenograft models recapitulate the radiological features of human adamantinomatous craniopharyngioma

Abstract

To assess the clinical relevance of transgenic and patient‐derived xenograft models of adamantinomatous craniopharyngioma (ACP) using serial magnetic resonance imaging (MRI) and high resolution post‐mortem microcomputed tomography (μ‐CT), with correlation with histology and human ACP imaging. The growth patterns and radiological features of tumors arising in Hesx1Cre/+;Ctnnb1lox(ex3)/+ transgenic mice, and of patient‐derived ACP xenografts implanted in the cerebral cortex, were monitored longitudinally in vivo with anatomical and functional MRI, and by ex vivo μ‐CT at study end. Pathological correlates with hematoxylin and eosin stained sections were investigated. Early enlargement and heterogeneity of Hesx1Cre/+;Ctnnb1lox(ex3)/+ mouse pituitaries was evident at initial imaging at 8 weeks, which was followed by enlargement of a solid tumor, and development of cysts and hemorrhage. Tumors demonstrated MRI features that recapitulated those of human ACP, specifically, T1‐weighted signal enhancement in the solid tumor component following Gd‐DTPA administration, and in some animals, hyperintense cysts on FLAIR and T1‐weighted images. Ex vivo μ‐CT correlated with MRI findings and identified smaller cysts, which were confirmed by histology. Characteristic histological features, including wet keratin and calcification, were visible on μ‐CT and verified by histological sections of patient‐derived ACP xenografts. The Hesx1Cre/+;Ctnnb1lox(ex3)/+ transgenic mouse model and cerebral patient‐derived ACP xenografts recapitulate a number of the key radiological features of the human disease and provide promising foundations for in vivo trials of novel therapeutics for the treatment of these tumors.

Patient‑derived orthotopic xenograft glioma models fail to replicate the magnetic resonance imaging features of the original patient tumor

“…Patient-derived glioblastoma xenograft models are a reliable translational platform that can recapitulate histopathological properties and maintain the genomic characteristics of parental tumors in situ (29). PDX adamantinomatous craniopharyngioma models recapitulate the radiological features of the original tumors (30).…”

Biological Behaviour of Craniopharyngiomas

“…The expression of a functionally equivalent form of stabilised β-catenin in either pituitary embryonic precursors or SOX2+ adult stem cells results in the formation of ACP-like tumours in mice [22, 23]. These tumours resemble some of the histological and radiological features of human ACP [24], but do not calcify or show wet keratin. A common characteristic in mouse and human ACP is that nucleocytoplasmic accumulation of β-catenin occurs only in sporadic cells, frequently forming cell clusters that overlap with the epithelial whorls previously described or dispersed throughout the tumour as single cells (Fig.…”

Characterization of the murine orthotopic adamantinomatous craniopharyngioma PDX model by MRI in correlation with histology

“…Processing of PDX mice (n = 27) for histological evaluation was performed as described elsewhere [ 19 – 21 ]. Following the MRI, the xenotransplanted animals were anesthetized with isofluorane and sacrificed by decapitation.…”

“…The preclinical testing of these targets in vivo makes suitable models indispensable [ 18 ]. Beside transgenic mouse models, the best conformance in relation to the human ACP was achieved using the intracranial xenograft model established from human tumor tissue [ 19 , 20 , 21 ]. The engrafted tumors may reproduce the complex 3D morphology of human ACP including all aforementioned non-vital (e.g.…”