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Published on: January 31, 2025
PTEN restrains SHH medulloblastma growth through cell autonomous and nonautonomous mechanisms
Zhimin Lao1, Salsabiel El Nagar1,2, Yinwen Liang1
1Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York 10065, NY, USA.
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 excellerates 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 were reduced in differentiated regions of tumors lacking Pten, indicating cell nonautonomous changes also contribute to accelerated tumor growth.
Insights
Loss of PTEN in Sonic hedgehog medulloblastoma (SHH-MB) accelerates tumor growth and differentiation. This suggests PTEN mutations may negatively impact SHH-MB patient outcomes, particularly germline mutations.
Area of Science:
- Neuro-oncology
- Cancer Genomics
- Developmental Biology
Background:
- Medulloblastoma (MB) is a pediatric brain tumor with distinct molecular subgroups.
- The Sonic hedgehog (SHH) signaling pathway is activated in a third of MB cases (SHH-MB).
- The role of secondary mutations, like those in PTEN, in SHH-MB severity is unclear.
Purpose of the Study:
- To investigate the impact of PTEN loss on tumor progression and differentiation in SHH-MB.
- To identify cellular and transcriptional changes associated with PTEN loss in SHH-MB.
Main Methods:
- Utilized sporadic SHH-MB mouse models with oncogenic SmoM2 expression in cerebellar granule cell precursors (GCPs).
- Induced heterozygous and homozygous loss of Pten in these models.
- Employed single-cell RNA sequencing (scRNA-seq) for cellular and transcriptional profiling.
Main Results:
- Homozygous Pten loss rapidly accelerated tumor growth and disease progression in SHH-MB mouse models.
- Heterozygous Pten loss led to increased proliferation and progenitor states initially, followed by rapid tumor differentiation.
- Loss of Pten reduced macrophage infiltration and cytotoxicity in differentiated tumor regions, suggesting non-autonomous effects.
Conclusions:
- PTEN mutations, especially germline, may negatively impact outcomes in SHH-MB.
- Loss of PTEN promotes rapid differentiation and altered tumor microenvironment in SHH-MB.
- Understanding PTEN's role is crucial for developing targeted therapies for SHH-MB.
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