TMOD-06. LOSS OF DICER COOPERATES WITH TUMOR SUPPRESSORS TO INITIATE METASTATIC MEDULLOBLASTOMA

Abstract To determine the role of microRNA regulation in brain tumor development, we incorporated a conditional allele of the microRNA processing enzyme Dicer to a previously characterized glioma mouse model based on inactivation of the tumor suppressors Nf1, Trp53, and Pten using the Nestin-creERT2 transgene. Loss of Dicer and tumor suppressors at adult ages led to glioma development; however, mutant mice tamoxifen induced at early postnatal ages developed medulloblastoma instead of glioma. The switch in tumor spectrum occurred with 100% penetrance and tumors were histologically indistinguishable from human medulloblastoma (MB). The minimum genetic mutations required for MB formation were Dicer and Trp53. Nf1 was dispensable, while additional loss of Pten produced more invasive tumors and leptomeningeal metastases. The time window for initiation of tumorigenesis was until the 2nd postnatal week, coinciding with the disappearance of the external granule layer (EGL), where cerebellar granule neuron precursors (CGNPs) undergo proliferation. Analysis of pre-symptomatic mutant mice showed proliferative defects and retained cells in the EGL, suggesting that the tumors may arise from CGNPs. However, targeting a subset of CGNPs using Math1-creERT2 did not lead to MB development, suggesting that an earlier EGL precursor may be required for tumorigenesis. Analysis of tumor transcriptome and MB subtype-specific genes and markers show that Dicer tumors most resemble extremely high risk p53-mutated SHH MB. Small RNA and mRNA sequencing analyses showed downregulation of microRNAs and dysregulation of its targets such as N-Myc. These studies demonstrate a role for microRNAs in MB development and show a fully penetrant genetic mouse model of highly metastatic MB.

Download Full-text

Oncogenic NRAS Accelerates Rhabdomyosarcoma Formation When Occurring within a Specific Time Frame during Tumor Development in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms222413377 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13377

Author(s):

Nada Ragab ◽

Julia Bauer ◽

Dominik S. Botermann ◽

Anja Uhmann ◽

Heidi Hahn

Keyword(s):

Mouse Model ◽

Tumor Growth ◽

Time Window ◽

Tumor Development ◽

Tumor Stage ◽

Time Frame ◽

Embryonal Rhabdomyosarcoma ◽

Tumor Differentiation ◽

Specific Time ◽

Free Survival

In the Ptch+/- mouse model for embryonal rhabdomyosarcoma (ERMS), we recently showed that oncogenic (onc) H-, K- or NRAS mutations do not influence tumor growth when induced at the advanced, full-blown tumor stage. However, when induced at the invisible ERMS precursor stage at 4 weeks of age, tumor development was enforced upon oncHRAS and oncKRAS but not by oncNRAS, which instead initiated tumor differentiation. These data indicate that oncRAS-associated processes differ from each other in dependency on the isoform and their occurrence during tumor development. Here, we investigated the outcome of oncNRAS induction at an earlier ERMS precursor stage at 2 weeks of age. In this setting, oncNRAS accelerates tumor growth because it significantly shortens the ERMS-free survival and increases the ERMS incidence. However, it does not seem to alter the differentiation of the tumors. It is also not involved in tumor initiation. Together, these data show that oncNRAS mutations can accelerate tumor growth when targeting immature ERMS precursors within a specific time window, in which the precursors are permissive to the mutation and show that oncNRAS-associated processes differ from each other in dependency on their occurrence during tumor development.

Download Full-text

1734-P: High Dietary Fat Intake Exacerbates Insulin Resistance in a Type 2 Diabetes Genetic Mouse Model

Diabetes ◽

10.2337/db20-1734-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1734-P

Author(s):

AUSTIN REILLY ◽

SHIJUN YAN ◽

ALEXA J. LONCHARICH ◽

HONGXIA REN

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Mouse Model ◽

Dietary Fat ◽

Fat Intake ◽

Dietary Fat Intake ◽

Genetic Mouse Model

Download Full-text

Faculty Opinions recommendation of Thyroid hormone receptors are tumor suppressors in a mouse model of metastatic follicular thyroid carcinoma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2028957.1604055 ◽

2010 ◽

Author(s):

Sissy Jhiang

Keyword(s):

Thyroid Hormone ◽

Mouse Model ◽

Thyroid Carcinoma ◽

Tumor Suppressors ◽

Hormone Receptors ◽

Follicular Thyroid Carcinoma ◽

Thyroid Hormone Receptors

Download Full-text

Faculty Opinions recommendation of RNAi-Based Gene Therapy Rescues Developmental and Epileptic Encephalopathy in a Genetic Mouse Model.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737854462.793574751 ◽

2020 ◽

Author(s):

Laurent Villard

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Epileptic Encephalopathy ◽

Genetic Mouse Model

Download Full-text

Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model

Nutrients ◽

10.3390/nu13041181 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1181

Author(s):

Raffaella Soleti ◽

Marine Coué ◽

Charlotte Trenteseaux ◽

Gregory Hilairet ◽

Lionel Fizanne ◽

...

Keyword(s):

Blood Pressure ◽

Mouse Model ◽

Aortic Root ◽

De Novo ◽

Body Weight Gain ◽

Density Lipoprotein ◽

De Novo Lipogenesis ◽

Hemodynamic Parameters ◽

Cellular Models ◽

Genetic Mouse Model

Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE−/−) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.

Download Full-text

Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis

Cancers ◽

10.3390/cancers13071515 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1515

Author(s):

Keiichiro Okuda ◽

Atsushi Umemura ◽

Shiori Umemura ◽

Seita Kataoka ◽

Hiroyoshi Taketani ◽

...

Keyword(s):

Mouse Model ◽

Glucocorticoid Receptor ◽

Nuclear Translocation ◽

Growth Factor Receptor ◽

Public Health Problem ◽

Egfr Signaling ◽

Alcoholic Steatohepatitis ◽

Genetic Mouse Model ◽

Treatment And Prevention ◽

Egfr Expression

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study’s clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased ERRFI1 mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased ERRFI1 expression. EGFR degradation or inactivation represents a novel approach for NASH–HCC treatment and prevention, and the GR–MIG6 axis is a newly defined target that can be activated by HNK and related compounds.

Download Full-text