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Identification, Histological Characterization, and Dissection of Mouse Prostate Lobes for In Vitro 3D Spheroid Culture Models
Published on: September 18, 2018
Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling
Jackie Wanjala1, Barry S Taylor2, Caren Chapinski1
1Human Oncology and Pathogenesis Oncology Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
Abstract:
Copy-number alterations (CNA) are among the most common molecular events in human prostate cancer genomes and are associated with worse prognosis. Identification of the oncogenic drivers within these CNAs is challenging due to the broad nature of these genomic gains or losses which can include large numbers of genes within a given region. Here, we profiled the genomes of four genetically engineered mouse prostate cancer models that reflect oncogenic events common in human prostate tumors, with the goal of integrating these data with human prostate cancer datasets to identify shared molecular events. Met was amplified in 67% of prostate tumors from Pten p53 prostate conditional null mice and in approximately 30% of metastatic human prostate cancer specimens, often in association with loss of PTEN and TP53. In murine tumors with Met amplification, Met copy-number gain and expression was present in some cells but not others, revealing intratumoral heterogeneity. Forced MET overexpression in non-MET-amplified prostate tumor cells activated PI3K and MAPK signaling and promoted cell proliferation and tumor growth, whereas MET kinase inhibition selectively impaired the growth of tumors with Met amplification. However, the impact of MET inhibitor therapy was compromised by the persistent growth of non-Met-amplified cells within Met-amplified tumors. These findings establish the importance of MET in prostate cancer progression but reveal potential limitations in the clinical use of MET inhibitors in late-stage prostate cancer.
Insights
Met amplification drives prostate cancer progression and is linked to poor prognosis. However, MET inhibitor therapy may be limited by tumor cell heterogeneity and resistance.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Copy-number alterations (CNAs) are frequent in prostate cancer and linked to worse outcomes.
- Identifying oncogenic drivers within large genomic regions of CNAs is difficult.
- Genetically engineered mouse models (GEMMs) can recapitulate human prostate cancer events.
Purpose of the Study:
- To identify shared molecular events in prostate cancer by integrating mouse model and human data.
- To investigate the role of MET amplification in prostate cancer progression.
- To evaluate the efficacy and limitations of MET inhibitors in prostate cancer.
Main Methods:
- Genome profiling of four GEMMs of prostate cancer.
- Integration of GEMM data with human prostate cancer datasets.
- Analysis of MET copy-number gain, expression, and signaling pathways (PI3K, MAPK).
- Assessment of MET inhibitor efficacy in preclinical models.
Main Results:
- Met amplification occurred in 67% of Pten p53 null mouse prostate tumors and ~30% of metastatic human prostate cancers.
- MET amplification was associated with PTEN and TP53 loss.
- Intratumoral heterogeneity in Met copy-number gain and expression was observed.
- MET overexpression activated PI3K/MAPK signaling, promoting proliferation.
- MET inhibition reduced tumor growth but was limited by resistant non-amplified cells.
Conclusions:
- MET is a significant driver in prostate cancer progression.
- MET amplification and associated signaling are critical for tumor growth.
- Intratumoral heterogeneity poses a challenge for MET inhibitor therapy in late-stage prostate cancer.
- Further strategies are needed to overcome resistance to MET inhibitors.
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