A New Player in Neuroblastoma: YAP and Its Role in the Neuroblastoma Microenvironment

Shim, Jenny; Goldsmith, Kelly

doi:10.3390/cancers13184650

Cited by 8 publications

(5 citation statements)

References 181 publications

(304 reference statements)

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“…Several studies showed that VPF-mediated YAP inhibition leads to a decrease in tumor cell proliferation, migration, and survival in vitro and suppression of tumor growth and progression in vivo 27,38,46,51 . With recent evidence of YAP/TAZ role in NB tumorigenicity, metastatic progression, treatment resistance and tumor relapse 13,14,17,18,52 , we aimed to investigate whether VPF can also be used as a potential therapeutic agent against NB.…”

Section: Discussionmentioning

confidence: 99%

Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression

Condurat

Aminzadeh-Gohari

Malnar

et al. 2023

Sci Rep

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Neuroblastoma (NB) is a highly aggressive extracranial solid tumor in children. Due to its heterogeneity, NB remains a therapeutic challenge. Several oncogenic factors, including the Hippo effectors YAP/TAZ, are associated with NB tumorigenesis. Verteporfin (VPF) is an FDA-approved drug shown to directly inhibit YAP/TAZ activity. Our study aimed to investigate VPF’s potential as a therapeutic agent in NB. We show that VPF selectively and efficiently impairs the viability of YAP/TAZ-expressing NB GI-ME-N and SK-N-AS cells, but not of non-malignant fibroblasts. To investigate whether VPF-mediated NB cell killing is YAP-dependent, we tested VPF potency in CRISPR-mediated YAP/TAZ knock-out GI-ME-N cells, and BE(2)-M17 NB cells (a MYCN-amplified, predominantly YAP-negative NB subtype). Our data shows that VPF-mediated NB cell killing is not dependent on YAP expression. Moreover, we determined that the formation of higher molecular weight (HMW) complexes is an early and shared VPF-induced cytotoxic mechanism in both YAP-positive and YAP-negative NB models. The accumulation of HMW complexes, involving STAT3, GM130 and COX IV proteins, impaired cell homeostasis and triggered cell stress and cell death mechanisms. Altogether, our study shows significant in vitro and in vivo VPF-induced suppression of NB growth, making VPF a potential therapeutic candidate against NB.

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Section: Discussionmentioning

confidence: 99%

Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression

Condurat

Aminzadeh-Gohari

Malnar

et al. 2023

Sci Rep

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show abstract

Section: Discussionmentioning

confidence: 99%

“…Recent studies have described the contribution of the Hippo tumor suppressor pathway downstream effectors YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif; WWTR1) in NB tumorigenesis, treatment resistance and relapse, highlighting the functional relevance of targeting YAP/TAZ in NB tumors [13][14][15][16][17][18][19][20][21][22] . YAP/TAZ are transcriptional co-activators that play a central role in stem cell modulation and tissue regeneration [23][24][25] .…”

Section: Introductionmentioning

confidence: 99%

Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression

Condurat

Aminzadeh-Gohari

Malnar

et al. 2022

Preprint

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Neuroblastoma (NB) is a highly aggressive extracranial solid tumor in children. Due to its heterogeneity, NB remains a therapeutic challenge. Several oncogenic factors, including the Hippo effectors YAP/TAZ, are associated with NB tumorigenesis. Verteporfin (VPF) is an FDA-approved drug shown to directly inhibit YAP/TAZ activity. Our study aimed to investigate VPF’s potential as a therapeutic agent in NB. We show that VPF selectively and efficiently impairs the viability of YAP/ TAZ-expressing NB GI-ME-N and SK-N-AS cells, but not of normal fibroblasts. To investigate whether VPF-mediated NB cell killing is YAP-dependent, we tested VPF potency in CRISPR-mediated YAP/TAZ knock-out GI-ME-N cells, as well as YAP-negative BE(2)-M17 NB cells. Our data shows that VPF-mediated NB cell killing is not dependent on YAP expression. Moreover, we determined that the formation of high molecular weight (HMW) complexes is an early and shared VPF-induced cytotoxic mechanism in both YAP-positive and YAP-negative NB models. The accumulation of HMW complexes, involving STAT3, GM130 and COX IV proteins, impaired cell homeostasis and triggered cell stress and cell death mechanisms. Altogether, our study shows significant in vitro and in vivo VPF-induced suppression of NB growth, making VPF a potential therapeutic candidate against NB.

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“…It is widely recognized that the crosstalk between tumor cells and stromal cells, such as fibroblasts and endothelial cells, contributes to tumor growth and progression. Increased expression/activity of the transcriptional co-regulator Yes-Associated Protein (YAP) following chemotherapy and relapse promotes resistance to therapy, including resistance to anti-disialoganglioside 2 (anti-GD2) immunotherapy, in high-risk neuroblastoma through the transcriptional repression of genes that play a role in the TME [ 41 , 42 ]. However, the role of YAP expression, as well as that of other factors in other solid tumors, has not been thoroughly evaluated.…”

Section: The Tme In Solid Tumorsmentioning

confidence: 99%

Pediatric Solid Cancers: Dissecting the Tumor Microenvironment to Improve the Results of Clinical Immunotherapy

Belgiovine,

Mebelli,

Raffaele

et al. 2024

IJMS

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Despite advances in their diagnosis and treatment, pediatric cancers remain among the leading causes of death in childhood. The development of immunotherapies and other forms of targeted therapies has significantly changed the prognosis of some previously incurable cancers in the adult population. However, so far, the results in pediatric cohorts are disappointing, which is mainly due to differences in tumor biology, including extreme heterogeneity and a generally low tumor mutational burden. A central role in the limited efficacy of immunotherapeutic approaches is played by the peculiar characteristics of the tumor microenvironment (TME) in pediatric cancer, with the scarcity of tumor infiltration by T cells and the abundance of stromal cells endowed with lymphocyte suppressor and tumor-growth-promoting activity. Thus, progress in the treatment of pediatric solid tumors will likely be influenced by the ability to modify the TME while delivering novel, more effective therapeutic agents. In this review, we will describe the TME composition in pediatric solid tumors and illustrate recent advances in treatment for the modulation of immune cells belonging to the TME.

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A New Player in Neuroblastoma: YAP and Its Role in the Neuroblastoma Microenvironment

Cited by 8 publications

References 181 publications

Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression

Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression

Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression

Pediatric Solid Cancers: Dissecting the Tumor Microenvironment to Improve the Results of Clinical Immunotherapy

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