scholarly journals HGG-11. LEPTOMENINGEAL DISEASE AND TUMOR DISSEMINATION ALONG CSF PATHWAYS IN A MURINE DIPG MODEL: IMPLICATIONS FOR STUDY OF THE TUMOR-CSF-EPENDYMAL MICROENVIRONMENT

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i19-i19
Author(s):  
Shelei Pan ◽  
Dezhuang Ye ◽  
Yimei Yue ◽  
Lihua Yang ◽  
Christopher Pacia ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Genetic Alterations ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Genetically Engineered ◽  
Leptomeningeal Disease ◽  
Tumor Spread ◽  
Csf Dissemination ◽  
Tumor Dissemination ◽  
Genetically Engineered Mouse Model ◽  
Ventricle Volume

Abstract Background Leptomeningeal disease and hydrocephalus are present in up to 30% of patients with diffuse intrinsic pontine glioma (DIPG), however there are no animal models of cerebrospinal fluid (CSF) dissemination. As the tumor-CSF-ependymal microenvironment may play an important role in tumor pathogenesis, we identified characteristics of the Nestin-tumor virus A (Nestin-Tva) genetically engineered mouse model (GEMM) that make it ideal to study the interaction of tumor cells with the CSF and its associated pathways with implications for the development of treatment approaches to address CSF dissemination in DIPG. Methods A Nestin-TVa model of DIPG utilizing the three most common DIPG genetic alterations (H3.3K27M, PDGF-B, p53) was used for this study. All animals underwent MR imaging and a subset underwent histopathologic analysis with H&E and beta-IV tubulin. Results Tumor dissemination within the CSF pathways (ventricles, leptomeninges) was present in 76% (25/33) of animals, with invasion of the choroid plexus, disruption of the ciliated ependyma and regional subependymal fluid accumulation. Ventricular enlargement consistent with hydrocephalus was present in 94% (31/33). Ventricle volume correlated with region specific transependymal CSF flow (periventricular T2 signal), localized anterior to the lateral ventricles. Subependymal tumor cells were also present subjacent to the 4th ventricle in a post-mortem human specimen. Conclusions This is the first study to report CSF pathway tumor dissemination an animal model of DIPG and is representative of CSF dissemination seen clinically. Understanding the CSF-tumor-ependymal microenvironment has significant implications for treatment of DIPG through targeting mechanisms of tumor spread within the CSF pathways.

scholarly journals DIPG-68. ALPHA-THALASSEMIA X-LINKED MENTAL RETARDATION PROTEIN (ATRX) LOSS-OF-FUNCTION IN A MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii300-iii300
Author(s):  
Chen Shen ◽  
David Picketts ◽  
Oren Becher
Keyword(s):  
Mouse Model ◽  
Pediatric Brain Tumor ◽  
High Grade Glioma ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Tumor Incidence ◽  
Loss Of Function ◽  
Nestin Expression ◽  
Genetically Engineered Mouse Model ◽  
Clinical Cases

Abstract Diffuse Intrinsic Potine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or efficacious therapies exist. Previous discoveries have revealed that, DIPG harbors distinct genetic alterations, when compared with adult high-grade glioma (HGG) or even with non-DIPG pediatric HGGs. ATRX alteration is found in 9% of clinical cases of DIPG, and significantly overlaps with H3.3K27M mutation and p53 loss, the two most common genetic changes in DIPG, found in 80% and 77% clinical cases, respectively. Here we developed genetically engineered mouse model of brainstem glioma using the RCAS-Tv-a system by targeting PDGF-B overexpression, p53 loss, H3.3K27M mutation and ATRX loss-of function to Nestin-expression brainstem progenitor cells of the neonatal mouse. Specifically, we used Nestin-Tv-a; p53 floxed; ATRX heterozygous female and Nestin-Tv-a; p53 floxed; ATRX floxed male breeders, generated offsprings with ATRX loss of function (n=18), ATRX heterozygous females (n=6), and ATRX WT (n=10). Median survial of the three groups are 65 days, 88 days and 51 days, respectively. Also, ATRX null mice is lower in tumor incidence (44.4%), compared with ATRX WT (80%). We evaluated the pathological features of DIPG with or without ATRX alteration, RNA-seq is performed to identify differentially expressed genes between ATRX WT and loss-of-function. In conclution, this study generated the first genetically modified mouse model studying ATRX loss-of-function in DIPG, and suggested that ATRX loss-of-function in DIPG may slow down tumorigenesis and decrease tumor incidence.

scholarly journals Characterization of Stem-like Circulating Tumor Cells in Pancreatic Cancer

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 305
Author(s):  
Lei Zhu ◽  
Barbara Hissa ◽  
Balázs Győrffy ◽  
Johann-Christoph Jann ◽  
Cui Yang ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Molecular Mechanisms ◽  
Genetically Engineered ◽  
Functional Enrichment ◽  
Ductal Adenocarcinoma ◽  
Free Survival ◽  
Dismal Prognosis ◽  
Genetically Engineered Mouse Model

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most frequent cause of death from cancer. Circulating tumor cells (CTCs) with stem-like characteristics lead to distant metastases and thus contribute to the dismal prognosis of PDAC. Our purpose is to investigate the role of stemness in CTCs derived from a genetically engineered mouse model of PDAC and to further explore the potential molecular mechanisms. The publically available RNA sequencing dataset GSE51372 was analyzed, and CTCs with (CTC-S) or without (CTC-N) stem-like features were discriminated based on a principal component analysis (PCA). Differentially expressed genes, weighted gene co-expression network analysis (WGCNA), and further functional enrichment analyses were performed. The prognostic role of the candidate gene (CTNNB1) was assessed in a clinical PDAC patient cohort. Overexpression of the pluripotency marker Klf4 (Krüppel-like factor 4) in CTC-S cells positively correlates with Ctnnb1 (β-Catenin) expression, and their interaction presumably happens via protein–protein binding in the nucleus. As a result, the adherens junction pathway is significantly enriched in CTC-S. Furthermore, the overexpression of Ctnnb1 is a negative prognostic factor for progression-free survival (PFS) and relapse-free survival (RFS) in human PDAC cohort. Overexpression of Ctnnb1 may thus promote the metastatic capabilities of CTCs with stem-like properties via adherens junctions in murine PDAC.

scholarly journals Differential Effects of Trp53 Alterations in Murine Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 808
Author(s):  
Alexander M. Betzler ◽  
Lahiri K. Nanduri ◽  
Barbara Hissa ◽  
Linda Blickensdörfer ◽  
Michael H. Muders ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Colorectal Carcinogenesis ◽  
Response To Treatment ◽  
Oncogenic Pathways ◽  
Genetically Engineered Mouse Model ◽  
Genetic Subtype ◽  
Genetic Landscape ◽  
Metastatic Capacity

Background: Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC. Methods: Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing. Results: The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC. Conclusions: This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.

scholarly journals HGG-17. FOCUSED ULTRASOUND-ENHANCED DELIVERY OF RADIOLABELED AGENTS TO DIFFUSE INTRINSIC PONTINE GLIOMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i20-i21
Author(s):  
Dezhuang Ye ◽  
Xiaohui Zhang ◽  
Lihua Yang ◽  
Yimei Yue ◽  
Yuan-chuan Tai ◽  
...  
Keyword(s):  
Half Life ◽  
Focused Ultrasound ◽  
Temporal Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Genetically Engineered ◽  
Pontine Glioma ◽  
Delivery Outcome ◽  
Efficient Delivery ◽  
Genetically Engineered Mouse Model ◽  
Tumor Virus

Abstract Diffuse intrinsic pontine glioma (DIPG) arising in the brainstem is the deadliest pediatric brain cancer with nearly 100% fatality and a median survival of <1 year. The critical location in the brainstem and the often intact blood-brain barrier (BBB) pose significant challenges in the treatment of DIPG. The objective of this study was to demonstrate the potential for focused ultrasound-induced BBB disruption (FUS-BBBD) to improve DIPG treatment by enhancing the safe and efficient delivery of drugs. A genetically engineered mouse model of DIPG was generated using the RCAS (replication-competent avian sarcoma-leucosis virus long-terminal repeat with splice acceptor)/tumor virus A modeling system. A magnetic resonance-guided FUS (MRgFUS) system was used to induce BBB disruption in these mice with the FUS targeted at the center of the tumor. Two radiolabeled agents with different sizes were used to evaluate the delivery efficiency of the FUS-BBBD technique in DIPG mice: a small-molecular radiotracer, 68Ga-DOTA-ECL1i, and a radiolabeled nanoparticle, 64Cu-labeled copper nanoparticles (64Cu-CuNCs, ~ 5 nm in diameter). 68Ga-DOTA-ECL1i (half-life ~ 1 h) and 64Cu-CuNCs (half-life ~13 h) were intravenously injected into the mice after FUS sonication, and microPET/CT imaging was performed at 1 h and 24 h, respectively, to evaluate the spatial-temporal distribution of these two agents in the brain and quantify the delivery outcome. FUS treatment increased the uptake of 68Ga-DOTA-ECL1i and 64Cu-CuNCs to the DIPG tumor by 3.25 folds and 4.07 folds on average, respectively. These findings demonstrated, for the first time, that FUS can increase BBB permeability in a murine model of DIPG and significantly enhance the delivery of agents of different sizes into the DIPG tumor.

scholarly journals Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Caroline Contat ◽  
Pierre-Benoit Ancey ◽  
Nadine Zangger ◽  
Silvia Sabatino ◽  
Justine Pascual ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Glucose Uptake ◽  
Tumor Cells ◽  
Fdg Pet ◽  
Glucose Transporter ◽  
Lamellar Body ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Model ◽  
18F Fdg

Glucose utilization increases in tumors, a metabolic process that is observed clinically by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET). However, is increased glucose uptake important for tumor cells, and which transporters are implicated in vivo? In a genetically-engineered mouse model of lung adenocarcinoma, we show that the deletion of only one highly expressed glucose transporter, Glut1 or Glut3, in cancer cells does not impair tumor growth, whereas their combined loss diminishes tumor development. 18F-FDG-PET analyses of tumors demonstrate that Glut1 and Glut3 loss decreases glucose uptake, which is mainly dependent on Glut1. Using 13C-glucose tracing with correlated nanoscale secondary ion mass spectrometry (NanoSIMS) and electron microscopy, we also report the presence of lamellar body-like organelles in tumor cells accumulating glucose-derived biomass, depending partially on Glut1. Our results demonstrate the requirement for two glucose transporters in lung adenocarcinoma, the dual blockade of which could reach therapeutic responses not achieved by individual targeting.

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