Related Experiment Video
Updated: Jul 15, 2026
Reconstruct Human Retinoblastoma In Vitro
Published on: October 11, 2022
Tumor-specific cooperation of retinoblastoma protein family and Snf5 inactivation
Jingjing Chai1, Xiangdong Lu, Virginia Godfrey
1Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
Abstract:
Malignant rhabdoid tumors (MRT) are rare aggressive cancers that occur in young children. Seventy-five percent of sporadic MRTs harbor inactivating SNF5 mutations, and mice heterozygous for an Snf5-null allele develop MRTs with partial penetrance. The diagnosis of choroid plexus carcinomas (CPC) in addition to MRTs in families with a single mutant SNF5 allele prompted us to assess the role of SNF5 loss in CPC in genetically engineered mice. With high frequency, TgT(121) mice develop CPCs that are initiated by inactivation of retinoblastoma protein (pRb) and related proteins p107 and p130. However, CPC penetrance and latency were not significantly affected by Snf5 heterozygosity, consistent with recent evidence that CPCs in SNF5 families were, in many cases, misdiagnosed MRTs. Surprisingly, although the CPC phenotype was unaffected, TgT(121);Snf5(+/-) mice developed MRTs with increased penetrance and decreased latency compared with TgT(121);Snf5(+/+) littermates. MRTs expressed the T(121) protein with a concomitant increase in mitotic activity. The predominant appearance of TgT(121);Snf5(+/-) MRTs in the spinal cord led to the discovery that these tumors likely arose from a subset of spinal cord neural progenitor cells expressing T(121) rather than from transdifferentiation of CPC. Significantly, the target cell type(s) for MRT is unknown. Hence, this study not only shows that pRb(f) and SNF5 inactivation cooperate to induce MRTs but also provides new insight into the MRT target population.
Insights
Loss of SNF5 cooperates with pRb inactivation to induce malignant rhabdoid tumors (MRTs) in mice. This study identifies spinal cord neural progenitor cells as a likely cell type for MRT development.
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers often linked to SNF5 mutations.
- Choroid plexus carcinomas (CPCs) have also been observed in families with SNF5 mutations, prompting investigation into SNF5's role.
- Retinoblastoma protein (pRb) pathway inactivation is implicated in CPC development.
Purpose of the Study:
- To investigate the role of SNF5 loss in the development of CPCs and MRTs in genetically engineered mouse models.
- To identify the cell of origin for MRTs.
- To understand the cooperative mechanisms between pRb pathway inactivation and SNF5 loss in tumorigenesis.
Main Methods:
- Utilized genetically engineered mice (TgT(121)) that develop CPCs due to pRb pathway inactivation.
- Assessed the impact of Snf5 heterozygosity (Snf5(+/-)) on CPC and MRT development in these mice.
- Analyzed tumor characteristics, including penetrance, latency, and cellular origin.
Main Results:
- Snf5 heterozygosity did not significantly affect CPC penetrance or latency in TgT(121) mice.
- TgT(121);Snf5(+/-) mice exhibited increased penetrance and decreased latency of MRTs compared to controls.
- MRTs predominantly appeared in the spinal cord, suggesting a specific neural progenitor cell origin rather than CPC transdifferentiation.
Conclusions:
- SNF5 inactivation cooperates with pRb pathway inactivation to induce MRTs with high frequency.
- CPCs in affected families may have been misdiagnosed MRTs.
- This study provides crucial insights into the target cell population for MRT development, pointing towards spinal cord neural progenitors.
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