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Structural or functional defects of PTEN in urothelial cells lacking P53 drive basal/squamous-subtype muscle-invasive
Feng He1, Fenglin Zhang2, Yi Liao2
1Department of Urology, New York University School of Medicine, New York, NY, 10016, USA; Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, NY, 10010, USA.
Abstract:
Muscle-invasive bladder cancer (MIBC) exhibits strong inter- and intra-tumor heterogeneity that affects biological behaviors, therapeutic responses, and prognoses. Mutations that activate RTK-RAS-PI3K and inactivate P19-P53-P21 coexist in 60-70% of MIBC. By time-controlled ablation of Tp53 and Pten, singly or combined, in adult mouse urothelium, we found that Tp53 loss alone produced no abnormality. While Pten loss elicited hyperplasia, it synergized with Tp53 loss to trigger 100% penetrant MIBC that exhibited basal/squamous features that resembled its human counterpart. Furthermore, PTEN was inactivated in human MIBC cell lines and specimens primarily by hyperphosphorylation of the C-terminus. Mutated or tailless PTEN incapable of C-terminal phosphorylation demonstrated increased inhibition of proliferation and invasion than full-length PTEN in cultured MIBC cells. In xenograft and transgenic mice, tailless PTEN, but not full-length PTEN, prevented further growth in established tumors. Collectively, deficiencies of both PTEN and P53 drive basal/squamous subtype MIBC. PTEN is inactivated by C-terminal hyperphosphorylation, and this modification may serve as a biomarker for subtyping MIBC and predicting tumor progression. Tailless PTEN is a potential molecular therapeutic for tumors, such as bladder cancer (BC), that can be readily accessed.
Insights
Loss of both P53 and PTEN tumor suppressors drives muscle-invasive bladder cancer (MIBC) with basal/squamous features. PTEN inactivation via C-terminal hyperphosphorylation may predict progression and guide therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Muscle-invasive bladder cancer (MIBC) displays significant heterogeneity impacting treatment and outcomes.
- Commonly, MIBC involves mutations activating RTK-RAS-PI3K pathways and inactivating P53 and P21.
- Understanding the genetic drivers of MIBC subtypes is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the roles of Tp53 and Pten loss in the development of MIBC.
- To explore the mechanism of PTEN inactivation in human MIBC.
- To evaluate the therapeutic potential of modified PTEN in bladder cancer models.
Main Methods:
- Time-controlled genetic ablation of Tp53 and Pten in adult mouse urothelium.
- Analysis of MIBC cell lines and patient specimens for PTEN alterations.
- Functional studies using cultured MIBC cells, xenografts, and transgenic mice with modified PTEN.
Main Results:
- Combined loss of Tp53 and Pten induced 100% penetrant MIBC with basal/squamous features in mice.
- Human MIBC frequently inactivates PTEN through C-terminal hyperphosphorylation.
- Tailless PTEN, unable to be phosphorylated, inhibited proliferation and invasion more effectively and prevented tumor growth in vivo.
Conclusions:
- Deficiencies in both PTEN and P53 are key drivers of the basal/squamous subtype of MIBC.
- PTEN C-terminal hyperphosphorylation serves as a potential biomarker for MIBC subtyping and progression prediction.
- Tailless PTEN represents a promising molecular therapeutic strategy for accessible tumors like bladder cancer.
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