A novel TAp73-inhibitory compound counteracts stemness features of glioblastoma stem cells
Javier Villoch-Fernandez1, Nicole Martínez-García2, Marta Martín-López3
1Instituto de Biomedicina y Departamento de Biología Molecular, Universidad de León, Spain.
Abstract:
Glioblastoma (GB) is the most common and fatal type of primary malignant brain tumor for which effective therapeutics are still lacking. GB stem cells, with tumor-initiating and self-renewal capacity, are mostly responsible for GB malignancy, representing a crucial target for therapies. The TP73 gene, which is highly expressed in GB, gives rise to the TAp73 isoform, a pleiotropic protein that regulates neural stem cell biology; however, its role in cancer has been highly controversial. We inactivated TP73 in human GB stem cells and revealed that TAp73 is required for their stemness potential, acting as a regulator of the transcriptional stemness signatures, highlighting TAp73 as a possible therapeutic target. As proof of concept, we identified a novel natural compound with TAp73-inhibitory capacity, which was highly effective against GB stem cells. The treatment reduced GB stem cell-invasion capacity and stem features, at least in part by TAp73 repression. Our data are consistent with a novel paradigm in which hijacking of p73-regulated neurodevelopmental programs, including neural stemness, might sustain tumor progression, pointing out TAp73 as a therapeutic strategy for GB.
Insights
TAp73 is crucial for glioblastoma stem cell survival and tumor growth. Inhibiting TAp73 with a new natural compound effectively targets these cancer stem cells, offering a promising glioblastoma therapeutic strategy.
Area of Science:
- Neuro-oncology
- Cancer Stem Cell Biology
- Molecular Therapeutics
Background:
- Glioblastoma (GB) is an aggressive brain tumor with limited treatment options.
- GB stem cells drive tumor progression and are key therapeutic targets.
- The role of the TP73 gene and its TAp73 isoform in cancer is controversial.
Purpose of the Study:
- To investigate the role of TAp73 in human glioblastoma stem cells.
- To identify TAp73 as a potential therapeutic target for glioblastoma.
- To evaluate a novel natural compound for its TAp73-inhibitory and anti-GB stem cell effects.
Main Methods:
- TP73 gene inactivation in human glioblastoma stem cells.
- Analysis of stemness signatures and cellular functions.
- In vitro testing of a novel natural compound with TAp73-inhibitory capacity.
Main Results:
- TAp73 is essential for maintaining the stemness and self-renewal of glioblastoma stem cells.
- TAp73 acts as a regulator of transcriptional stemness signatures in glioblastoma.
- A novel natural compound effectively inhibited TAp73, reducing glioblastoma stem cell invasion and stem features.
Conclusions:
- TAp73 plays a critical role in glioblastoma stemness and progression.
- Targeting TAp73 represents a novel therapeutic strategy for glioblastoma.
- A TAp73-inhibitory natural compound shows significant potential against glioblastoma stem cells.
