A Mutant p53-Dependent Embryonic Stem Cell Gene Signature Is Associated with Augmented Tumorigenesis of Stem Cells

Area of Science:

• Oncology
• Cancer Stem Cell Biology
• Molecular Oncology

Background:

• Mutations in the tumor suppressor p53 are common in human cancers, including inactivating and gain-of-function (GOF) types that promote tumor progression.
• Cancer stem cells (CSCs) drive tumor initiation, metastasis, and relapse, posing a significant therapeutic challenge.
• Targeting CSCs and their associated stemness features is crucial for effective cancer treatment.

Purpose of the Study:

• To investigate the role of mutant p53 in conferring stemness features to mesenchymal stem cells (MSCs).
• To identify molecular mechanisms underlying the aggressive tumor-forming capabilities of mutant p53-derived MSCs.
• To explore the potential of identified molecular signatures as prognostic biomarkers and therapeutic targets in human cancers.

Main Methods:

• Cultivation of tumors from mutant p53 murine bone marrow MSCs to generate aggressive tumor lines (MSCs-TLs).
• Comparative analysis of MSC-TLs and parental mutant p53 MSCs to identify molecular events.
• Assessment of CSC markers, oncogenicity, and embryonic stem cell (ESC) gene signature expression.
• Evaluation of the impact of mutant p53 knockout on tumor development and gene signature expression.
• Correlation analysis of MSC-TL ESC signature genes with patient survival and p53 mutation status in human cancers.

Main Results:

• In vitro cultivation of mutant p53 MSCs generated aggressive MSC-TLs with CSC features, high oncogenicity, and CSC marker expression.
• MSC-TLs exhibited a specific ESC gene signature not present in parental cells.
• Knockout of mutant p53 reduced tumor development, CSC frequency, CSC markers, and the ESC signature.
• Genes within the MSC-TL ESC signature correlated with poor patient survival and were upregulated in human tumors with p53 hotspot mutations.

Conclusions:

• Mesenchymal stem cell-like tumor lines derived from mutant p53 MSCs possess CSC characteristics.
• A mutant p53-dependent ESC gene signature is associated with aggressive tumor behavior and CSC features.
• This ESC gene signature represents a potential stemness-based prognostic biomarker and a novel therapeutic target in cancers harboring p53 mutations.