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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Pten knockout affects drug resistance differently in melanoma and kidney cancer
Klaudia Brodaczewska1, Aleksandra Majewska2,3, Aleksandra Filipiak-Duliban2,3
1Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Szaserów 128, 01-141, Warsaw, Poland. kbrodaczewska@wim.mil.pl.
Background:
PTEN is a tumor suppressor that is often mutated and nonfunctional in many types of cancer. The high heterogeneity of PTEN function between tumor types makes new Pten knockout models necessary to assess its impact on cancer progression and/or treatment outcomes.
Methods:
We aimed to show the effect of CRISPR/Cas9-mediated Pten knockout on murine melanoma (B16 F10) and kidney cancer (Renca) cells. We evaluated the effect of PTEN deregulation on tumor progression in vivo and in vitro, as well as on the effectiveness of drug treatment in vitro. In addition, we studied the molecular changes induced by Pten knockout.
Results:
In both models, Pten mutation did not cause significant changes in cell proliferation in vitro or in vivo. Cells with Pten knockout differed in sensitivity to cisplatin treatment: in B16 F10 cells, the lack of PTEN induced sensitivity and, in Renca cells, resistance to drug treatment. Accumulation of pAKT was observed in both cell lines, but only Renca cells showed upregulation of the p53 level after Pten knockout. PTEN deregulation also varied in the way that it altered PAI-1 secretion in the tested models, showing a decrease in PAI-1 in B16 F10 Pten/KO and an increase in Renca Pten/KO cells. In kidney cancer cells, Pten knockout caused changes in epithelial to mesenchymal transition marker expression, with downregulation of E-cadherin and upregulation of Snail, Mmp9, and Acta2 (α-SMA).
Conclusions:
The results confirmed heterogenous cell responses to PTEN loss, which may lead to a better understanding of the role of PTEN in particular types of tumors and points to PTEN as a therapeutic target for personalized medicine.
Insights
Loss of PTEN (Phosphatase and tensin homolog) tumor suppressor function impacts cancer drug sensitivity differently across tumor types. Pten knockout in melanoma cells increased cisplatin sensitivity, while kidney cancer cells became resistant, highlighting PTEN
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- PTEN is a critical tumor suppressor frequently inactivated in various cancers.
- Tumor-specific heterogeneity in PTEN function necessitates novel Pten knockout models for comprehensive analysis.
- Understanding PTEN's role is vital for cancer progression and treatment outcome assessment.
Purpose of the Study:
- To investigate the impact of CRISPR/Cas9-mediated Pten knockout on murine melanoma (B16 F10) and kidney cancer (Renca) cells.
- To evaluate PTEN deregulation effects on tumor progression in vitro and in vivo.
- To assess PTEN loss influence on drug treatment efficacy and molecular alterations.
Main Methods:
- CRISPR/Cas9 gene editing to create Pten knockout models in B16 F10 and Renca cell lines.
- In vitro and in vivo assays to evaluate tumor progression and cell proliferation.
- Analysis of molecular changes, including pAKT, p53, PAI-1, and epithelial-to-mesenchymal transition markers.
Main Results:
- Pten knockout did not significantly alter cell proliferation in either model.
- Differential drug sensitivity observed: B16 F10 cells showed increased sensitivity to cisplatin, while Renca cells exhibited resistance.
- Molecular changes included pAKT accumulation in both, p53 upregulation in Renca, altered PAI-1 secretion, and EMT marker changes in Renca cells.
Conclusions:
- PTEN loss elicits heterogeneous cellular responses, underscoring its complex role in different cancer types.
- Findings support PTEN as a potential therapeutic target for personalized cancer medicine.
- Further research into PTEN's context-dependent functions is warranted.
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