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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
p18Ink4c and p53 Act as tumor suppressors in cyclin D1-driven primitive neuroectodermal tumor
Raya Saab1, Carlos Rodriguez-Galindo, Kelly Matmati
1Children's Cancer Center of Lebanon, American University of Beirut Medical Center, Beirut, Lebanon. rs88@aub.edu.lb
Abstract:
The retinoblastoma (RB) tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10% to 15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in association with cyclin-dependent kinase (Cdk) 4 and Cdk6 phosphorylates and inactivates the RB protein, is expressed in 40% of sporadic medulloblastoma, a PNET of the cerebellum. To understand tumorigenic events cooperating with RB pathway disruption in brain PNET, we generated a transgenic mouse where cyclin D1 was expressed in pineal cells. Cyclin D1 enhanced pinealocyte proliferation, causing pineal gland enlargement. However, proliferation ceased beyond 2 weeks of age with reversal of Cdk4-mediated Rb phosphorylation despite continued expression of the transgene, and the pineal cells showed heterochromatin foci suggestive of a senescent-like state. In the absence of the p53 tumor suppressor, cell proliferation continued, resulting in pineal PNET that limited mouse survival to approximately 4 months. Interestingly, the Cdk inhibitor p18(Ink4c) was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, although at an older age than those lacking p53. Analogous to our mouse model, we found that children with heritable RB often had asymptomatic pineal gland enlargement that only rarely progressed to PNET. Our finding that the Cdk4 inhibitor p18(Ink4c) is a tumor suppressor in cyclin D1-driven PNET suggests that pharmacologic interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary RB pathway disruption.
Insights
Retinoblastoma (RB) pathway disruption contributes to brain tumors. Overexpression of cyclin D1 in mice led to pineal gland enlargement and, without p53, pineal PNET, suggesting Cdk4 inhibition as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The retinoblastoma (RB) tumor suppressor pathway plays a critical role in cell cycle regulation and is frequently disrupted in various cancers.
- Primitive neuroectodermal tumors (PNETs) of the brain, including medulloblastoma, are aggressive pediatric brain tumors.
- RB pathway alterations are implicated in PNET development, with a subset of patients developing brain PNETs.
Purpose of the Study:
- To investigate the cooperative roles of RB pathway disruption and cyclin D1 overexpression in the development of brain PNETs.
- To elucidate the molecular mechanisms underlying PNET tumorigenesis in a mouse model.
- To identify potential therapeutic targets for RB pathway-driven PNETs.
Main Methods:
- Generation of a transgenic mouse model with cyclin D1 expression specifically in pineal cells.
- Analysis of cell proliferation, RB phosphorylation, and senescence markers in response to cyclin D1 overexpression.
- Evaluation of tumor development and survival in mice with genetic alterations in RB pathway components (p53, p18Ink4c).
Main Results:
- Cyclin D1 overexpression in pineal cells induced proliferation and gland enlargement, followed by a senescent-like state.
- Absence of the p53 tumor suppressor led to continuous proliferation and the development of aggressive pineal PNETs.
- The Cdk inhibitor p18(Ink4c) was induced independently of p53, and its absence promoted invasive PNET development at an older age.
- Human data showed asymptomatic pineal gland enlargement in individuals with heritable RB, with rare progression to PNET.
Conclusions:
- RB pathway disruption cooperates with cyclin D1 to drive PNET development.
- p53 and p18(Ink4c) act as crucial tumor suppressors in cyclin D1-driven PNETs.
- Inhibition of Cdk4 activity presents a potential chemoprevention or therapeutic strategy for RB pathway-disrupted cancers.
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