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Wnt pathway in atypical teratoid rhabdoid tumors
Madhavi Chakravadhanula1, Chris N Hampton1, Parth Chodavadia1
1Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, Arizona (M.C., C.N.H., V.O., R.D.B.); Children's Hospital at Westmead, Sydney, Australia (L.Z., D.C.); Duke University, Durham, North Carolina (P.C.); Children's Hospital Los Angeles, Los Angeles, California (A.E.-E.); Children's Hospital Los Angeles and the University of Southern California, Los Angeles, California (J.X., A.E.-E.).
Background:
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive pediatric brain tumor with limited therapeutic options. The hypothesis for this study was that the Wnt pathway triggered by the Wnt5B ligand plays an important role in ATRT biology. To address this hypothesis, the role of WNT5B and other Wnt pathway genes was analyzed in ATRT tissues and ATRT primary cell lines.
Methods:
Transcriptome-sequencing analyses were performed using nanoString platforms, immunohistochemistry, Western blotting, quantitative reverse transcriptase PCR, immunoprecipitation, short interference RNA studies, cell viability studies, and drug dose response (DDR) assays.
Results:
Our transcriptome-sequencing results of Wnt pathway genes from ATRT tissues and cell lines indicated that the WNT5B gene is significantly upregulated in ATRT samples compared with nontumor brain samples. These results also indicated a differential expression of both canonical and noncanonical Wnt genes. Imunoprecipitation studies indicated that Wnt5B binds to Frizzled1 and Ryk receptors. Inhibition of WNT5B by short interference RNA decreased the expression of FRIZZLED1 and RYK. Cell viability studies a indicated significant decrease in cell viability by inhibiting Frizzled1 receptor. DDR assays showed promising results with some inhibitors.
Conclusions:
These promising therapeutic options will be studied further before starting a translational clinical trial. The success of these options will improve care for these patients.
Insights
Wnt5B ligand is upregulated in atypical teratoid rhabdoid tumors (ATRTs), a pediatric brain cancer. Inhibiting Wnt5B and its receptors shows promise for new ATRT therapies.
Area of Science:
- Pediatric oncology
- Molecular biology
- Cancer research
Background:
- Atypical teratoid rhabdoid tumor (ATRT) is a rare and aggressive pediatric brain tumor.
- Current therapeutic strategies for ATRT are limited, necessitating novel treatment approaches.
Purpose of the Study:
- To investigate the role of the Wnt signaling pathway, specifically the Wnt5B ligand, in ATRT biology.
- To analyze the expression of WNT5B and other Wnt pathway genes in ATRT tissues and cell lines.
Main Methods:
- Transcriptome sequencing (nanoString)
- Immunohistochemistry
- Western blotting
- Quantitative reverse transcriptase PCR
- Immunoprecipitation
- Short interference RNA (siRNA) studies
- Cell viability assays
- Drug dose response (DDR) assays
Main Results:
- WNT5B gene expression is significantly upregulated in ATRT samples compared to non-tumor brain tissue.
- Wnt5B was found to bind to Frizzled1 and Ryk receptors.
- Inhibition of WNT5B via siRNA reduced Frizzled1 and Ryk expression.
- Inhibiting the Frizzled1 receptor significantly decreased ATRT cell viability.
- Drug dose response assays indicated potential efficacy of certain inhibitors.
Conclusions:
- The Wnt5B pathway plays a significant role in ATRT pathogenesis.
- Targeting WNT5B and its associated receptors presents a promising therapeutic strategy for ATRT.
- Further research and clinical trials are warranted to translate these findings into effective patient treatments.
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