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Related Concept Videos

Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

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Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
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Rous Sarcoma Virus (RSV) and Cancer01:03

Rous Sarcoma Virus (RSV) and Cancer

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Rous Sarcoma virus or RSV was discovered by F. Peyton Rous in the year 1911 as a filterable transmissible agent that could cause tumors in chickens. He won a Nobel Prize for this discovery in 1966. His experiments clearly demonstrated that some cancers could be caused by infectious agents and led to the discovery of many more cancer-causing viruses in animals as well as humans.
RSV is a retrovirus that contains two copies of a plus-strand  RNA genome. Its genome consists of four main open...
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Abnormal Proliferation02:23

Abnormal Proliferation

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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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The Retinoblastoma Gene01:20

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Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
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Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

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Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
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Such genes that act...
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In-vitro Mutagenesis01:16

In-vitro Mutagenesis

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To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.
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Related Experiment Video

Updated: Aug 13, 2025

Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells

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VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis.

Sarah Watson1, Collette A LaVigne2, Lin Xu3

  • 1Institut Curie Research Center, Paris Sciences et Lettres (PSL) Research University, INSERM U830, 75005 Paris, France; Institut Curie, Paris Sciences et Lettres (PSL) Research University, Medical Oncology Department, 75005 Paris, France.

Cell Reports
|January 19, 2023
PubMed
Summary
This summary is machine-generated.

The VGLL2-NCOA2 gene fusion drives infantile rhabdomyosarcoma by activating developmental pathways. Targeting ARF6, a key player in these pathways, presents a potential therapeutic strategy for sarcomas.

Keywords:
CP: Cancercross-species comparative oncologydevelopmental biologyfunctional genomicsfusion oncogenepediatric cancerrhabdomyosarcoma

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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
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Area of Science:

  • Oncology
  • Genetics
  • Developmental Biology

Background:

  • Clinical sequencing identifies numerous sarcoma gene fusions lacking functional validation.
  • The VGLL2-NCOA2 fusion, observed in infantile rhabdomyosarcoma, exemplifies such a fusion.
  • Understanding the functional role of VGLL2-NCOA2 is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the tumorigenic mechanisms of the VGLL2-NCOA2 fusion.
  • To identify potential therapeutic vulnerabilities associated with VGLL2-NCOA2.
  • To utilize a cross-species comparative oncology approach for comprehensive analysis.

Main Methods:

  • Employing zebrafish models for functional studies of VGLL2-NCOA2.
  • Utilizing mouse allograft models to assess tumor development and recapitulation of human disease.
  • Analyzing patient samples to validate findings from preclinical models.
  • Performing transcriptional profiling of tumors to identify associated developmental programs.

Main Results:

  • VGLL2-NCOA2 is sufficient to induce mesenchymal tumors with immature skeletal muscle features, mirroring human rhabdomyosarcoma.
  • Transcriptional analysis revealed VGLL2-NCOA2 tumors engage embryonic somitogenesis and developmental programs, including the RAS family GTPase ARF6.
  • ARF6 demonstrated high expression across zebrafish, mouse, and patient-derived tumors.
  • ARF6 knockout inhibited VGLL2-NCOA2's oncogenic activity in vitro, and ARF6 overexpression was noted in various pediatric and adult sarcomas.

Conclusions:

  • VGLL2-NCOA2 functions as an oncogene by hijacking developmental programs for tumor formation.
  • The reactivation or persistent expression of ARF6 represents a significant therapeutic vulnerability in sarcomas driven by VGLL2-NCOA2.
  • Targeting ARF6 may offer a novel therapeutic strategy for patients with specific sarcoma subtypes.