Genetically engineered mouse models of craniopharyngioma: an opportunity for therapy development and understanding of tumor biology

Apps, John; Martinez-Barbera, Juan Pedro

doi:10.1111/bpa.12501

Cited by 15 publications

(7 citation statements)

References 45 publications

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“…To test the effects of trametinib in the mouse model, we cultured neoplastic pituitaries at P1 in the presence or absence of 2 and 20 nM trametinib for 18 h ( n = 6 pituitaries). P1 neoplastic pituitaries resemble human ACP more closely than older stages of murine tumour development at both the histological and molecular levels [ 4 , 17 , 40 ]. Immunofluorescence revealed an obvious decrease in p-ERK1/2 immunofluorescence within the neoplastic pituitaries upon trametinib treatment with both concentrations, which was more apparent at 20 nM, demonstrating the successful inhibition of the MAPK/ERK pathway (Fig.…”

Section: Resultsmentioning

confidence: 99%

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target

et al. 2018

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Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1830-2) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target

et al. 2018

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“…This results in a degradation-resistant form of beta-catenin, resulting in aberrant nuclear accumulation of the protein in certain cells within the tumor. In the nucleus, beta-catenin acts as a transcription factor, leading to overactivation of the WNT/beta-catenin pathway [16,18,19]. Although this aberrant overactivation of the WNT pathway is thought to be crucial in the pathogenesis of ACPs, the resulting nuclear accumulation of beta-catenin is only observed in a minority of cells, specifically in whorl like epithelial cell clusters ( Figure 1D).…”

Section: The Central Role Of Wnt Pathway Overactivation In the Tumorimentioning

confidence: 99%

The Inflammatory Milieu of Adamantinomatous Craniopharyngioma and Its Implications for Treatment

Whelan

Prince

Gilani

et al. 2020

JCM

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Pediatric Adamantinomatous Craniopharyngiomas (ACPs) are histologically benign brain tumors that often follow an aggressive clinical course. Their suprasellar location leaves them in close proximity to critical neurological and vascular structures and often results in significant neuroendocrine morbidity. Current treatment paradigms, involving surgical resection and radiotherapy, confer significant morbidity to patients and there is an obvious need to discover effective and safe alternative treatments. Recent years have witnessed significant efforts to fully detail the genomic, transcriptomic and proteomic make-up of these tumors, in an attempt to identify potential therapeutic targets. These studies have resulted in ever mounting evidence that inflammatory processes and the immune response play a critical role in the pathogenesis of both the solid and cystic portion of ACPs. Several inflammatory and immune markers have been identified in both the cyst fluid and solid tumor tissue of ACP. Due to the existence of effective agents that target them, IL-6 and immune checkpoint inhibitors seem to present the most likely immediate candidates for clinical trials of targeted immune-related therapy in ACP. If effective, such agents may result in a paradigm shift in treatment that ultimately reduces morbidity and results in better outcomes for our patients.

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“…Only one craniopharyngioma in mice has been reported, which was diagnosed to be malignant. A genetically modified mouse model of benign craniopharyngioma has been developed ( Apps and Martinez-Barbera, 2017 ). The morphology of the induced tumors resembled the features for ameloblastomas of the teeth.…”

Section: Pituitarymentioning

confidence: 99%

“…( Anderson and Capen 1978 ; Apps and Martinez-Barbera 2017 ; Botts et al 1994 ; Capen 1996a ; Capen et al 2001 ; Carlton and Gries 1996 ; Fitzgerald et al 1971 ; Heider 1986 )…”

Section: Pituitarymentioning

confidence: 99%

Nonproliferative and Proliferative Lesions of the Rat and Mouse Endocrine System

Brändli-Baiocco

Balme

Bruder³

et al. 2018

J Toxicol Pathol

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The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative among the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the endocrine organs (pituitary gland, pineal gland, thyroid gland, parathyroid glands, adrenal glands and pancreatic islets) of laboratory rats and mice, with color photomicrographs illustrating examples of the lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for endocrine lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

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Genetically engineered mouse models of craniopharyngioma: an opportunity for therapy development and understanding of tumor biology

Cited by 15 publications

References 45 publications

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target

The Inflammatory Milieu of Adamantinomatous Craniopharyngioma and Its Implications for Treatment

Nonproliferative and Proliferative Lesions of the Rat and Mouse Endocrine System

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