Synthetic Lethality Through GSK3 Inhibition in Glioma Stem Cells via the WNT-WWC1-YAP Axis

doi:10.21203/rs.3.rs-5227114/v1

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Synthetic Lethality Through GSK3 Inhibition in Glioma Stem Cells via the WNT-WWC1-YAP Axis

https://doi.org/10.21203/rs.3.rs-5227114/v1

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Glioblastoma (GBM) is an aggressive brain tumor driven by glioma stem cells (GSCs), which contribute to tumor growth and therapeutic resistance. This study investigates the effects of GSK3 inhibition on GSC viability, focusing on the role of the canonical WNT signaling pathway. We found that GSK3 inhibition activates the WNT pathway, leading to upregulation of Wwc1, which downregulates Yap via LATS1 phosphorylation. This reduces GSC proliferation, self-renewal, and enhances chemosensitivity. Analysis of clinical datasets revealed that WNT pathway activation correlates with improved prognosis in proneural gliomas, particularly in IDH1-mutated tumors. Our findings suggest that targeting the WNT-Wwc1-YAP axis, particularly through GSK3 inhibition, could induce synthetic lethality in GSCs and provide a promising therapeutic strategy for gliomas. These results highlight the potential of exploiting WNT-induced synthetic lethality as a novel approach for glioma treatment.

Biological sciences/Cancer/CNS cancer

Biological sciences/Cancer/Cancer therapy/Chemotherapy

Gliomas are among the most common and aggressive neoplasms of the central nervous system, with glioblastoma (GBM) being the most malignant and prevalent subtype, accounting for more than half of all diagnosed gliomas. GBM is notorious for its invasive nature, rapid progression and resistance to conventional therapies, resulting in a median survival of approximately one year despite aggressive treatment regimens¹. Advances in molecular profiling have led to the classification of gliomas into distinct subtypes, such as the proneural and mesenchymal subtypes, each characterized by unique molecular and clinical features. The proneural subtype, which is often associated with mutations such as IDH1, is generally associated with a more favorable prognosis compared to the more aggressive mesenchymal subtype^2,3.

A pivotal cellular population within gliomas, termed glioma stem cells (GSCs), possess the ability to self-renew and sustain tumor growth, suggesting that they play a fundamental role in glioma recurrence and treatment failure^4-6. As such, GSCs represent a critical target for therapeutic intervention. These cells can be cultured in vitro under serum-free conditions so that they retain their stem-like properties and tumorigenic potential, providing a robust model system for studying glioma biology and evaluating potential therapeutic strategies^7,8.

Among the various developmental pathways involved in the maintenance of GSCs and gliomagenesis, the canonical WNT signaling pathway has emerged as a major player⁹. The canonical WNT pathway is initiated when WNT ligands bind to Frizzled receptors, leading to stabilization of β-catenin by inhibiting the APC/Axin/GSK3β destruction complex¹⁰. In many cancers, aberrant activation of the WNT pathway is associated with increased tumorigenesis, proliferation and metastasis^10,11. However, in certain malignancies such as medulloblastoma, WNT pathway activation has been correlated with better clinical outcomes, in part due to its effects on tumor vasculature to enhanced delivery of chemotherapeutic agents¹².

Recent studies have further elucidated the complexity of WNT signaling in cancer and have shown that overactivation of the pathway can lead to synthetic lethality in some cases. For instance, Chang et al. demonstrated that in colorectal cancer, overactivation of the WNT pathway can lead to tumor cell death via synthetic-lethal interactions¹³. This raises the intriguing possibility that a similar mechanism could be present in tumors of the central nervous system, even though the molecular basis is still poorly understood.

In this study, we investigate the effects of GSK3 inhibition on the viability and chemosensitivity of GSCs, focusing particularly on the canonical WNT signaling pathway. GSK3 inhibition stabilizes β-catenin, leading to upregulation of Wwc1, a key regulator of the Hippo pathway. Wwc1 promotes phosphorylation of LATS1, resulting in downregulation of Yap, a transcriptional co-activator involved in cell proliferation and survival. This downregulation of Yap leads to decreased GSC proliferation, decreased c-MYC signaling and increased chemosensitivity. Furthermore, our analysis of clinical datasets reveals that activation of the WNT pathway is predominantly observed in the proneural subtype of gliomas, particularly in IDH1-mutated tumors with a G-CIMP signature, where it is associated with improved patient outcomes. These results provide new mechanistic insights into the WNT-Wwc1-Yap axis in glioma biology and synthetic-lethal interactions, suggesting a novel therapeutic approach to improve the efficacy of chemotherapy in gliomas.

GSK3 inhibition reduces the viability of glioma stem cells and induces cell death

To identify potential therapeutic targets in glioma stem cells (GSCs), we performed a small-scale screening with small molecules from the signal transduction small molecules in the murine glioma stem cell line HTS⁶. Among the compounds tested, CHIR99021 (CHIR), a highly specific GSK3 inhibitor, significantly reduced the viability of HTS⁶ cells as well as other murine and human glioma stem cell lines (Fig. 1A). Importantly, CHIR exhibited no cytotoxic effects on primary astrocytes derived from neonatal C57/B6 mice (Fig. 1B). This selective inhibition of GSCs by CHIR was recapitulated with LiCl, another GSK3 inhibitor, in a concentration-dependent manner (Supplementary Fig. 1).

We further investigated the effects of CHIR on cell death and proliferation in HTS cells. CHIR treatment induced robust cell death, as determined by Annexin V staining (Fig. 1C, D), and significantly decreased cell proliferation, as determined by EdU incorporation assays (Fig. 1E & F). These results indicate that inhibition of GSK3 effectively impairs GSC viability by inducing both cell death and proliferation arrest.

GSK3β, but not GSK3α, is crucial for the growth of glioma stem cells

GSK3 is present in mammalian cells in the form of two paralogs, GSK3α and GSK3β. To determine which paralog is essential for GSC survival, we employed shRNA-mediated knockdown of GSK3α and GSK3β in HTS cells. Knockdown of GSK3β sensitized HTS cells to CHIR-induced growth inhibition, whereas knockdown of GSK3α had no significant effect on cell viability (Fig. 2A & B). Given these results, we focused on GSK3β for subsequent experiments. Knockdown of GSK3β by shRNA delayed the growth of HTS cells by reducing their proliferative capacity (Fig. 2C-E), but had minimal impact on apoptosis (Supplementary Fig. 2). Notably, knockdown of GSK3β significantly diminished sphere formation in HTS cells in terms of both the frequency and sphere size (Fig. 2F-H), indicating that GSK3β is critical for the self-renewal properties of GSCs. In vivo, knockdown of GSK3β in HTS cells prolonged the survival of tumor-bearing mice (Fig. 2I), further supporting its role as a key regulator of GSC-driven tumorigenesis.

Activation of the canonical WNT pathway mediates the effects of GSK3 inhibition

Given that GSK3β is a key component of the β-catenin destruction complex, we hypothesized that the canonical WNT pathway mediates the cytotoxic effects of GSK3 inhibition in GSCs. To test this hypothesis, we generated HTS6 cells overexpressing a constitutively active form of β-catenin (CTN*) or a dominant-negative form of TCF (dTCF), the latter of which blocks β-catenin activity (Fig. 3A, Supplementary Fig. 3A). Activation of the WNT pathway through CTN* overexpression sensitized HTS6 cells to CHIR, whereas blocking the pathway by dTCF rescued cell viability (Fig. 3B). These results suggest that the GSK3β-β-catenin axis plays a central role in mediating the inhibitory effect of CHIR on GSCs.

Overexpression of CTN* in HTS6 cells phenocopied the effects of GSK3β knockdown by reducing cell proliferation and self-renewal capacity in vitro (Fig. 3C-E, Supplementary Fig. 3B-D) and prolonging survival in tumor-bearing mice (Fig. 3F). These findings suggest that canonical WNT signaling is sufficient to affect the viability and tumorigenic potential of GSC, similar to the phenomena observed by Chang et al. in colon cancer cells¹³.

Activation of the WNT signaling pathway correlates with better prognosis in glioma patients

To investigate the clinical relevance of our findings, we performed a single-sample gene set enrichment analysis (ssGSEA)¹⁴ using RNA-seq data from The Cancer Genome Atlas (TCGA)¹⁵ and the Chinese Glioma Genome Atlas (CGGA)¹⁶. In both datasets, activation of the canonical WNT pathway was associated with a significantly better prognosis in glioma patients (Fig. 4A, B, Supplementary Fig. 4A). Expression of the WNT ligands WNT7A and WNT7B, which are highly expressed in the brain, was inversely correlated with glioma grade, and lower expression of WNT7B was predictive of poorer patient survival (Supplementary Fig. 4B-E).

Furthermore, we observed that the majority of IDH1-mutated tumors with a CpG island methylator phenotype (G-CIMP)¹⁷ and a large proportion of tumors classified as proneural subtype exhibited high canonical WNT activity, whereas mesenchymal gliomas showed low WNT activity (Fig. 4C, Supplementary Fig. 4F, G). This subtype-specific enrichment of WNT activity correlates well with clinical outcomes, as both G-CIMP and proneural gliomas are known to confer a better prognosis^2,16.

To investigate whether high levels of canonical WNT signaling may be involved in the maintenance of the subtype of GSCs, we treated two proneural human GSCs in the presence of CHIR with TNFα, which is known to promote the mesenchymal subtype¹⁸, in the presence of CHIR. Consistent with previous reports, TNFα treatment increased the expression level of the mesenchymal marker CD44, and this effect can be attenuated by additional CHIR (Fig. 4D), suggesting that activation of WNT signaling helps GSCs to maintain a proneural signature.

WNT activation promotes Wwc1 expression and represses Yap via LATS1 activation

To uncover the downstream mechanisms by which WNT activation inhibits GSC growth, we performed a microarray analysis comparing gene expression in HTS6 cells expressing CTN* or dTCF under different concentrations of CHIR (Fig. 5A). Wwc1 emerged as a key candidate whose expression correlated with CHIR-induced cytotoxicity. Using real-time PCR, we confirmed that the expression of Wwc1 was significantly upregulated in HTS6 cells treated with 10 or 20 µM CHIR, but remained unchanged at 5 µM CHIR, a concentration that had no effect on viability. In contrast, expression of the canonical WNT target gene Axin2 increased continuously with increasing CHIR concentration (Fig. 5B).

Overexpression of CTN* also induced Wwc1 expression, whereas dTCF repressed it, supporting the role of β-catenin in regulating Wwc1 transcription (Fig. 5B). Western blot analysis confirmed that CHIR treatment increased Wwc1 protein levels (Fig. 5C). We identified multiple TCF4 binding sites within the Wwc1 promoter, and deletion of these sites abrogated CTN*-induced Wwc1 expression, confirming that β-catenin directly regulates Wwc1 transcription (Fig. 5D & E). Furthermore, silencing Wwc1 expression by shRNA in HTS cells partially abrogated the cytotoxicity of high concentrations of CHIR (Fig. 5F & G).

In glioma samples, Wwc1 expression correlates inversely with the degree of tumor grades and is significantly more pronounced in patient samples with higher WNT activity (Fig. 5H & I). Similar to activation of canonical WNT signaling, higher Wwc1 expression in gliomas is associated with a significantly better prognosis in both the TCGA and CGGA datasets (Fig. 5J and Supplementary Fig. 5).

Wwc1 is a known regulator of the Hippo pathway, where it modulates LATS1 phosphorylation to repress Yap activity^19-21. Consistent with this, CHIR treatment increased LATS1 phosphorylation in HTS6 cells (Fig. 6A), leading to subsequent phosphorylation and degradation of Yap (Fig. 6B & C). Overexpression of CTN* or knockdown of GSK3β also decreased Yap protein levels, whereas overexpression of dTCF reversed this effect (Fig. 6D & E). Silencing of LATS1/2 or overexpression of YapS127A partially rescued CHIR-induced cell death, further confirming the role of LATS1-Yap signaling in mediating the cytotoxic effects of WNT activation (Fig. 6G & H).

To further investigate the relationship between WNT activation and Yap downregulation in a clinical setting, we examined the level of the Yap target gene CTGF in medulloblastoma, as a molecular subtype of medulloblastoma is associated with WNT activation^22,23. Consistent with our observation, the WNT subgroup of medulloblastoma has the lowest CTGF level, while the SHH subset, which is reported to be associated with Yap amplification and upregulation, has the highest CTGF level²⁴ (Fig. 6I). A similar trend has been observed in glioma patient samples: CTGF expression was lower in tumors with higher WNT activity; its expression correlated positively with tumor grade and predicted worse outcome (Fig. 6J-L). Histologically, we found that tumor samples showing high expression of WNT7B also showed high expression of the proneural marker OLIG2, but relatively low expression of the mesenchymal marker CD44 and the Yap target gene CTGF (Fig. 6M).

To investigate the role of Yap in GSCs, we knocked down Yap with shRNAs and found decreased HTS cell growth (Fig. 7A-E) and significantly decreased sphere formation ability (Fig. 7F). GSEA analysis revealed that Myc targets and cell cycle related E2F targets were significantly downregulated (Fig. 7G). Yap was reported to directly regulate Myc expression²⁵ and high concentration of CHIR treatment resulted in downregulation of c-myc level in HTS cells (Fig. 7H). Many studies have shown that overexpression of Yap is associated with chemoresistance^26,27. Consistent with previous observations, HTS cells in which either Gsk3b or Yap expression was downregulated showed higher sensitivity to the chemotherapeutic agents carboplatin and 5FU (Fig. 7I & J).

Since CHIR requires a relatively high concentration to show cytotoxicity on glioma cells, we screened several known GSK3 inhibitors and found that alsterpaullone (ALP) was 5-10-fold more potent than CHIR (Fig. 8A). Similar to CHIR and other GSK3 inhibitors, ALP can also activate the WNT reporter (Fig. 8B). It can also downregulate Yap protein levels at 1 μM (Fig. 8C). In vivo, ALP treatment delays the growth of tumor allografts compared to the DMSO control group (Fig. 8D, E, Supplementary Fig. 8A & B).

The canonical WNT signaling pathway is well established as a driving force for tumorigenesis and metastasis in various cancers^10,11. Activation of the WNT pathway often leads to increased proliferation, invasion and resistance to apoptosis, contributing to poor outcomes in these malignancies. However, recent studies have highlighted a more nuanced role of WNT signaling. There is evidence that hyperactivation of this signaling pathway can lead to cell death in some cases, a phenomenon known as conditional synthetic lethality. In colorectal cancer, for instance, hyperactivation of WNT signaling in APC-mutated cells leads to synthetic lethality, highlighting a therapeutic vulnerability¹³. Despite these findings, the role of this mechanism in central nervous system (CNS) tumors, including gliomas, remains largely unexplored.

In fact, clinical observations in some tumors suggest that activation of the WNT pathway is associated with a better prognosis for patients^28,29. In primary melanoma, for example, WNT activation is associated with improved survival and a lower likelihood of metastasis³⁰. Similarly, GSK3 inhibition, which stabilizes β-catenin and activates the WNT pathway, has been shown to inhibit melanoma cell growth in vitro and in vivo²⁸. In medulloblastoma, the subtype defined by activation of the WNT pathway has the most favorable prognosis. More than 95% of patients under 16 years of age survive longer than 5 years²⁰. This improved prognosis is attributed to WNT-induced changes in the tumor vasculature that improve the penetration and efficacy of chemotherapeutic agents¹². However, the direct effects and mechnisms of WNT signaling on the tumor cells themselves, particularly in gliomas, have not yet been thoroughly investigated.

In this study, we observed a similar association between activation of the WNT signaling pathway and improved prognosis in gliomas, consistent with findings in medulloblastomas and melanomas. Specifically, we found that gliomas with high canonical WNT activity had increased IDH1 mutations, exhibited a glioma CpG island methylator phenotype (G-CIMP), and were primarily classified as a proneural subtype, all of which are associated with a more favorable prognosis^2,16. Although the exact mechanisms underlying this relationship are still unclear, our findings suggest a possible tumor suppressive role of WNT pathway activation in gliomas.

One possible explanation may lie in the role of WNT signaling in neuronal differentiation during development. Activation of the WNT pathway has been shown to promote neuronal differentiation, while the Yap protein, a key regulator of cell proliferation, is known to promote neural progenitor cell expansion and is downregulated during differentiation^31,32. Remarkably, forced upregulation of Yap can reprogram differentiated neurons back to a progenitor-like state³³. In line with these developmental roles, our data show that WNT activation in glioma stem cells (GSCs) results in the downregulation of Yap through the induction of Wwc1, which in turn activates the Hippo signaling pathway. This downregulation of Yap reduces the self-renewal capacity of GSCs and sensitizes them to chemotherapy. This suggests that the WNT-Wwc1-Yap axis plays a critical role in regulating GSC viability and therapeutic response in gliomas.

The mechanism of synthetic lethality due to WNT overactivation remains unclear. Our study suggests that the interaction between WNT and the Hippo signaling pathway may play an important role in this process. Yap can act as either an inhibitor or an activator of WNT/β-catenin signaling, depending on its cellular localization and interaction with cofactors, including β-catenin itself³⁴. However, the reciprocal regulation of Yap by WNT signaling is still less well understood. Our findings extend current knowledge by demonstrating that nuclear β-catenin binds directly to the Wwc1 promoter, thereby affecting the LATS-Yap axis and contributing to the regulation of Yap protein levels. This regulatory mechanism appears to be tissue-specific, as we observed no significant effect of GSK3 inhibitor (CHIR) treatment on WNT-dependent colon cancer cell lines such as HCT116. In contrast, similar regulatory effects on Yap expression and cell viability were observed in the melanoma cell line A375, where CHIR treatment reduced Yap levels and impaired tumor growth (Supplementary Fig. 7 & Fig. 8).

In the context of gliomas, our data suggest that transcriptional regulation of Wwc1 by β-catenin is a critical step in modulating the WNT-Yap axis. Remarkably, Wwc1 expression is highly enriched in the brain, a finding that may explain why this regulatory mechanism is particularly pronounced in brain tumors³⁵. Interestingly, unlike AXIN2, which is consistently upregulated in response to increasing β-catenin levels, Wwc1 expression requires a higher threshold of β-catenin activation in glioma stem cells. This threshold-dependent activation could reflect a unique regulatory mechanism in gliomas that warrants further investigation.

Our findings also suggest that the effects of GSK3 inhibition on glioma cell viability may be associated with both off-target toxicity and increased chemosensitivity. While GSK3 inhibitors have been shown to affect the sensitivity of cancer cells to various chemotherapeutic agents, the underlying mechanisms remain poorly understood³⁶. Our study suggests that downregulation of Yap following GSK3 inhibition may contribute to this increased chemosensitivity, as high Yap expression has been associated with cancer cell survival and resistance to chemotherapy^26,27.

Our study provides valuable insights into the role of WNT signaling in glioma stem cell biology demonstrating that pathway activation via the WNT-Wwc1-Yap axis can trigger conditional synthetic lethality. Importantly, our findings suggest that this synthetic lethality may exhibit tissue specificity, particularly in CNS tumors. These results suggest that targeting the WNT signaling pathway—particularly by inhibiting GSK3 — may represent a promising therapeutic strategy, especially for gliomas of the proneural subtype harboring IDH1 mutations. By elucidating the molecular mechanisms underlying WNT-induced chemosensitivity, this study contributes to the growing body of evidence for the context-dependent dual role of WNT signaling in cancer. Furthermore, it underscores the potential of exploiting synthetic lethal interactions as a novel therapeutic approach in gliomas and possibly other cancers.

Competing interests: The authors declare that they have no competing interests

Authors' contributions: F.F.R., X.Z. L., T.L. and Y.L.Y performed the experiments. J.C. designed the experiments. F.F.R., L.F.P. and J.C. analyzed the data and wrote the paper.

Acknowledgements: The authors thank Dr. Wei Mo for HTS cells and Dr. Shangfeng Gao for GBM paraffin sections. This work was supported by National Key R&D Program of China (SQ2022YFA1100106, 2016YFA0503100), National Natural Science Foundation of China Grants (81502392, 8132687, 31501137), Thousand Youth Talents Plan grant and by Major Project for Natural Science research in Jiangsu Province (17KJA320004) and Jiangsu Basic Research Funds for Young Scientists BK20150351.

Ostrom, Q. T. et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015-2019. Neuro Oncol 24, v1-v95, doi:10.1093/neuonc/noac202 (2022).
Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98-110, doi:10.1016/j.ccr.2009.12.020 (2010).
Wang, Q. et al. Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell 33, 152, doi:10.1016/j.ccell.2017.12.012 (2018).
Xie, X. P. et al. Quiescent human glioblastoma cancer stem cells drive tumor initiation, expansion, and recurrence following chemotherapy. Dev Cell 57, 32-46.e38, doi:10.1016/j.devcel.2021.12.007 (2022).
Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522-526, doi:10.1038/nature11287 (2012).
Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396-401, doi:10.1038/nature03128 (2004).
Min, W. et al. Multi-omics and Pharmacological Characterization of Patient-derived Glioma Cell Lines. bioRxiv, 2023.2002.2020.529198, doi:10.1101/2023.02.20.529198 (2023).
Shi, Y. et al. Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. Nature 567, 341-346, doi:10.1038/s41586-019-0993-x (2019).
Takebe, N., Harris, P. J., Warren, R. Q. & Ivy, S. P. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 8, 97-106, doi:10.1038/nrclinonc.2010.196 (2011).
Nusse, R. & Clevers, H. Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell 169, 985-999, doi:10.1016/j.cell.2017.05.016 (2017).
Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13, 11-26, doi:10.1038/nrc3419 (2013).
Phoenix, T. N. et al. Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype. Cancer Cell 29, 508-522, doi:10.1016/j.ccell.2016.03.002 (2016).
Chang, L. et al. Systematic profiling of conditional pathway activation identifies context-dependent synthetic lethalities. Nature Genetics 55, 1709-1720, doi:10.1038/s41588-024-01680-3 (2023).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102, 15545-15550, doi:10.1073/pnas.0506580102 (2005).
Cancer Genome Atlas Research, N. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068, doi:10.1038/nature07385 (2008).
Zhao, Z. et al. Comprehensive RNA-seq transcriptomic profiling in the malignant progression of gliomas. Sci Data 4, 170024, doi:10.1038/sdata.2017.24 (2017).
Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510-522, doi:10.1016/j.ccr.2010.03.017 (2010).
Bhat, K. P. L. et al. Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell 24, 331-346, doi:10.1016/j.ccr.2013.08.001 (2013).
Zhong, Z., Jiao, Z. & Yu, F. X. The Hippo signaling pathway in development and regeneration. Cell Rep 43, 113926, doi:10.1016/j.celrep.2024.113926 (2024).
Baumgartner, R., Poernbacher, I., Buser, N., Hafen, E. & Stocker, H. The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev Cell 18, 309-316, doi:10.1016/j.devcel.2009.12.013 (2010).
Yu, J. et al. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell 18, 288-299, doi:10.1016/j.devcel.2009.12.012 (2010).
Ellison, D. W. et al. Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121, 381-396, doi:10.1007/s00401-011-0800-8 (2011).
Northcott, P. A. et al. Medulloblastoma. Nat Rev Dis Primers 5, 11, doi:10.1038/s41572-019-0063-6 (2019).
Fernandez, L. A. et al. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev 23, 2729-2741, doi:10.1101/gad.1824509 (2009).
Ren, F. et al. Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration. Cell Res 23, 1133-1146, doi:10.1038/cr.2013.101 (2013).
Kapoor, A. et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158, 185-197, doi:10.1016/j.cell.2014.06.003 (2014).
Shao, D. D. et al. KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 158, 171-184, doi:10.1016/j.cell.2014.06.004 (2014).
Atkinson, J. M. et al. Activating the Wnt/beta-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3. PLoS One 10, e0125028, doi:10.1371/journal.pone.0125028 (2015).
Korur, S. et al. GSK3beta regulates differentiation and growth arrest in glioblastoma. PLoS One 4, e7443, doi:10.1371/journal.pone.0007443 (2009).
Kageshita, T. et al. Loss of beta-catenin expression associated with disease progression in malignant melanoma. Br J Dermatol 145, 210-216, doi:10.1046/j.1365-2133.2001.04336.x (2001).
Hirabayashi, Y. et al. The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development 131, 2791-2801, doi:10.1242/dev.01165 (2004).
Cao, X., Pfaff, S. L. & Gage, F. H. YAP regulates neural progenitor cell number via the TEA domain transcription factor. Genes Dev 22, 3320-3334, doi:10.1101/gad.1726608 (2008).
Panciera, T. et al. Induction of Expandable Tissue-Specific Stem/Progenitor Cells through Transient Expression of YAP/TAZ. Cell Stem Cell 19, 725-737, doi:10.1016/j.stem.2016.08.009 (2016).
Hansen, C. G., Moroishi, T. & Guan, K. L. YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol 25, 499-513, doi:10.1016/j.tcb.2015.05.002 (2015).
Guske, K. et al. Tissue-specific differences in the regulation of KIBRA gene expression involve transcription factor TCF7L2 and a complex alternative promoter system. J Mol Med (Berl) 92, 185-196, doi:10.1007/s00109-013-1089-y (2014).
Thorne, C. A. et al. GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors. Nat Chem Biol 11, 58-63, doi:10.1038/nchembio.1690 (2015).

There is NO conflict of interest to disclose.

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Synthetic Lethality Through GSK3 Inhibition in Glioma Stem Cells via the WNT-WWC1-YAP Axis

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