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PTEN restrains SHH medulloblastoma growth through cell autonomous and nonautonomous mechanisms
Zhimin Lao1, Salsabiel El Nagar1, Yinwen Liang1
1Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
Abstract:
A third of patients with the pediatric cerebellar tumor Medulloblastoma (MB) have mutations that activate Sonic hedgehog (SHH) signaling (SHH-MB subgroup). The contribution of secondary mutations to tumor severity, however, is not clear. PTEN mutations are enriched in the SHH-1 subtype that has the lowest survival rate. Widespread heterozygous loss of Pten in two SHH-MB mouse models increases penetrance and accelerates onset of differentiated tumors. We delineated cellular and transcriptional changes that accelerate tumor growth and cause differentiation using a sporadic SHH-MB mouse model expressing oncogenic SmoM2 in rare cerebellar granule cell precursors (GCPs) and scRNA-seq analysis. Homozygous but not heterozygous sporadic loss of Pten resulted in rapid acceleration of tumor growth and end-stage disease by 40 days, compared to ~25% survival in control SmoM2 mice at 100 days. Heterozygous PTEN mutations, therefore, should negatively impact disease outcome primarily with germline mutations. Loss of Pten in normal or SmoM2-expressing GCPs increased proliferation and enhanced progenitor state initially, but by 12 days Pten mutant SmoM2 tumors were highly differentiated due to increased survival of non-proliferating GCPs. Furthermore, macrophage infiltration and cytotoxicity appeared reduced in differentiated regions of tumors lacking Pten, indicating cell nonautonomous changes could also contribute to accelerated tumor growth.
Insights
Secondary PTEN mutations accelerate Sonic hedgehog medulloblastoma growth and differentiation in mice. Loss of PTEN in these pediatric brain tumors impacts survival and tumor progression, highlighting potential therapeutic targets.
Area of Science:
- Neuro-oncology
- Cancer Genomics
- Pediatric Oncology
Background:
- Medulloblastoma (MB) is a common pediatric brain tumor, with the Sonic hedgehog (SHH) subgroup accounting for a third of cases.
- Secondary mutations, particularly in PTEN, are linked to poorer outcomes in the aggressive SHH-MB subtype.
- The precise role of PTEN mutations in SHH-MB progression and tumor severity remains unclear.
Purpose of the Study:
- To investigate the impact of PTEN loss on tumor growth, differentiation, and cellular changes in SHH-MB mouse models.
- To delineate the cellular and transcriptional mechanisms driving accelerated tumor progression and differentiation upon PTEN mutation.
- To assess the contribution of heterozygous versus homozygous PTEN loss to SHH-MB development.
Main Methods:
- Utilized two SHH-MB mouse models with widespread heterozygous Pten loss.
- Employed a sporadic SHH-MB mouse model with oncogenic SmoM2 expression in cerebellar granule cell precursors (GCPs).
- Performed single-cell RNA sequencing (scRNA-seq) analysis to characterize cellular and transcriptional alterations.
Main Results:
- Homozygous Pten loss significantly accelerated tumor growth and progression to end-stage disease by 40 days in the sporadic model.
- Heterozygous Pten loss increased tumor penetrance and accelerated differentiation.
- Pten loss initially enhanced GCP proliferation but led to highly differentiated tumors by 12 days due to increased survival of non-proliferating cells. Macrophage infiltration and cytotoxicity were reduced in Pten-deficient tumors.
Conclusions:
- PTEN loss, particularly homozygous loss, dramatically accelerates SHH-MB progression and differentiation.
- Heterozygous PTEN mutations negatively impact disease outcome, especially with germline mutations.
- Cell nonautonomous mechanisms, including reduced macrophage infiltration, may contribute to accelerated tumor growth in PTEN-mutant SHH-MB.
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