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De Novo Generation of Somatic Stem Cells by YAP/TAZ
Published on: May 7, 2018
WIP-YAP/TAZ as A New Pro-Oncogenic Pathway in Glioma
Sergio Rivas1,2,3,4, Inés M Antón5,6,7, Francisco Wandosell8,9
1Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain. srivas@cnb.csic.es.
Abstract:
Wild-type p53 (wtp53) is described as a tumour suppressor gene, and mutations in p53 occur in many human cancers. Indeed, in high-grade malignant glioma, numerous molecular genetics studies have established central roles of RTK-PI3K-PTEN and ARF-MDM2-p53 INK4a-RB pathways in promoting oncogenic capacity. Deregulation of these signalling pathways, among others, drives changes in the glial/stem cell state and environment that permit autonomous growth. The initially transformed cell may undergo subsequent modifications, acquiring a more complete tumour-initiating phenotype responsible for disease advancement to stages that are more aggressive. We recently established that the oncogenic activity of mutant p53 (mtp53) is driven by the actin cytoskeleton-associated protein WIP (WASP-interacting protein), correlated with tumour growth, and more importantly that both proteins are responsible for the tumour-initiating cell phenotype. We reported that WIP knockdown in mtp53-expressing glioblastoma greatly reduced proliferation and growth capacity of cancer stem cell (CSC)-like cells and decreased CSC-like markers, such as hyaluronic acid receptor (CD44), prominin-1 (CD133), yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). We thus propose a new CSC signalling pathway downstream of mtp53 in which Akt regulates WIP and controls YAP/TAZ stability. WIP drives a mechanism that stimulates growth signals, promoting YAP/TAZ and β-catenin stability in a Hippo-independent fashion, which allows cells to coordinate processes such as proliferation, stemness and invasiveness, which are key factors in cancer progression. Based on this multistep tumourigenic model, it is tantalizing to propose that WIP inhibitors may be applied as an effective anti-cancer therapy.
Insights
Mutant p53 (mtp53) drives cancer stem cell (CSC) phenotypes via the WIP protein, promoting proliferation and invasiveness. Targeting WIP may offer a novel anti-cancer therapy for glioblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Biology
Background:
- Mutations in the p53 tumor suppressor gene are common in human cancers, including high-grade malignant glioma.
- Signaling pathways like RTK-PI3K-PTEN and ARF-MDM2-p53 are crucial for glioma development and progression.
- Cancer stem cells (CSCs) drive tumor initiation, growth, and therapeutic resistance.
Purpose of the Study:
- To investigate the role of mutant p53 (mtp53) and its associated proteins in driving the tumor-initiating cell phenotype in glioblastoma.
- To elucidate a novel signaling pathway downstream of mtp53 that regulates CSC properties.
- To explore the therapeutic potential of targeting WIP in mtp53-driven cancers.
Main Methods:
- Utilized glioblastoma models expressing mutant p53.
- Performed WIP knockdown experiments to assess effects on cancer stem cell properties.
- Analyzed expression of CSC markers (CD44, CD133, YAP, TAZ) and signaling pathway components (Akt, WIP, YAP/TAZ, β-catenin).
Main Results:
- Mutant p53 oncogenic activity is driven by WASP-interacting protein (WIP), which is essential for the tumor-initiating cell phenotype.
- WIP knockdown in mtp53-expressing glioblastoma cells significantly reduced proliferation, growth, and CSC marker expression.
- A novel mtp53-downstream pathway involving Akt-WIP-mediated regulation of YAP/TAZ stability was identified, promoting proliferation, stemness, and invasiveness independently of the Hippo pathway.
Conclusions:
- WASP-interacting protein (WIP) is a critical driver of the oncogenic activity of mutant p53 (mtp53) and promotes cancer stem cell phenotypes.
- Targeting WIP represents a promising therapeutic strategy for treating mtp53-driven cancers, particularly glioblastoma.
- The identified mtp53-WIP-YAP/TAZ signaling axis offers new insights into glioblastoma progression and potential therapeutic interventions.
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