Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1

Mabe, Nathaniel W.; Huang, Min; Dalton, Guillermo Nicolás; Alexe, Gabriela; Schaefer, Daniel A.; Geraghty, Anna C.; Robichaud, Amanda L.; Conway, Amy Saur; Khalid, Delan; Mader, Marius Marc-Daniel; Ross, Kenneth N.; Sheffer, Michal; Linde, Miles H.; Ly, Nghi; Yao, Winnie; Rotiroti, Maria Caterina; Smith, Benjamin; Wernig, Marius; Bertozzi, Carolyn R.; Monje, Michelle; Mitsiades, Constantine S.; Majeti, Ravindra; Satpathy, Ansuman T.; Stegmaier, Kimberly; Majzner, Robbie G.

doi:10.1038/s43018-022-00405-x

Cited by 29 publications

(39 citation statements)

References 69 publications

(83 reference statements)

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“…Thus, we suggest that global changes in H3K27Ac and H3K27me3 regulated by ECM topography reflect epigenetic modification in ADRN signatures specifically, not MES signatures. This finding may be consistent with a previous report suggesting that EZH2 inhibitor, suppressing H3K27me3 globally, promotes the ADRN subtype(30). Our data was corroborated further by GSEA looking at ADRN genes associated with differentially accessible peaks, showing preferential enrichment in open chromatin peaks across ADRN genes for NB cells on flat control versus NGA substrate (Fig.…”

Section: Main Textsupporting

confidence: 94%

Extracellular matrix topography drives adrenergic to mesenchymal transition in neuroblastoma

Chronopoulos,

Vemula,

Chavez

et al. 2023

Preprint

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Neuroblastoma (NB), the most common extracranial solid tumor in children, exhibits significant intra-tumoral heterogeneity with two interconvertible identities: adrenergic (ADRN) and mesenchymal (MES). MES cells ex-hibit phenotypes associated with metastasis and are enriched in relapse NB compared to ADRN. Thus, repro-gramming from ADRN to MES may determine inferior NB outcomes, which needs better elucidation. Extracel-lular matrix (ECM) is an essential tumor microenvironment (TME) component that provides physical support as a scaffold and delivers mechanical cues. We demonstrate that high-risk NB has more topographically aligned ECM fibers than low-risk NB. Using nano-fabricated biomaterials mimicking ECM alignment, we reveal that ECM topography drives ADRN-MES reprogramming by enhancing cell-ECM interactions. This transition in-volves epigenetic and transcriptional changes, accompanied by enhanced phenotypic features of MES. Also, we uncover that ECM-driven reprogramming relies on the Rho-associated kinase pathway. Overall, ECM-driven ADRN-MES reprogramming provides insight into TME-targeted therapeutic strategies for suppressing MES and improving NB outcomes.

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Section: Main Textsupporting

confidence: 94%

Extracellular matrix topography drives adrenergic to mesenchymal transition in neuroblastoma

Chronopoulos,

Vemula,

Chavez

et al. 2023

Preprint

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“…Another exciting avenue for future study of EZH2 inhibition is as an adjuvant to immunotherapy. Specifically, recent studies have shown that EZH2 inhibition can increase tumor expression of the disialoganglioside GD2 and enhance efficacy of anti-GD2 therapies ( Kailayangiri et al, 2019 ; Mabe et al, 2022 ). Given the efficacy of GD2-directed chimeric antigen receptor (CAR) T-cells in DMG preclinical research and promising early data from clinical trials, combination with EZH2 inhibition and other epigenetic therapies is a strategy worthy of further investigation ( Mount et al, 2018 ; Majzner et al, 2022 ).…”

Section: Epigenetic Programming and Combination Strategiesmentioning

confidence: 99%

Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit

Groves

Cooney

2022

Front. Cell Dev. Biol.

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Pediatric high-grade gliomas (pHGG) are a molecularly diverse group of malignancies, each incredibly aggressive and in dire need of treatment advancements. Genomic analysis has revolutionized our understanding of these tumors, identifying biologically relevant subgroups with differing canonical mutational profiles that vary based on tumor location and age. In particular, the discovery of recurrent histone H3 mutations (H3K27M in diffuse midline glioma, H3G34R/V in hemispheric pediatric high-grade gliomas) as unique “oncohistone” drivers revealed epigenetic dysregulation as a hallmark of pediatric high-grade gliomas oncogenesis. While reversing this signature through epigenetic programming has proven effective in several pre-clinical survival models, early results from pediatric high-grade gliomas clinical trials suggest that epigenetic modifier monotherapy will likely not provide long-term disease control. In this review we summarize the genetic, epigenetic, and cellular heterogeneity of pediatric high-grade gliomas, and highlight potential paths forward for epigenetic programming in this devastating disease.

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“…An improvement of GD2 expression on tumor cells could enhance anti-GD2 mAbs efficacy without a dose-escalation. Thus, strategies to increase GD2 expression on tumor cells or to enhance the sensitivity of tumor cells to the effects of anti-GD2 mAbs are actively sought to make tolerable doses of mAbs able to provide better clinical results [ 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Naxitamab Activity in Neuroblastoma Cells Is Enhanced by Nanofenretinide and Nanospermidine

et al. 2023

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Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is also expressed in neurons, skin melanocytes, and peripheral nerve fibers. Immunotherapy with monoclonal anti-GD2 antibodies has a proven efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. However, the strong neuro-toxicity associated with anti-GD2 antibodies administration has hindered, until now, the possibility for dose-escalation and protracted use, thus restraining their therapeutic potential. Strategies to increase the efficacy of anti-GD2 antibodies are actively sought, with the aim to enable chronic treatments that could eradicate minimal residual disease and subsequent relapses, often occurring after treatment. Here, we report that Nanofenretinide and Nanospermidine improved the expression of GD2 in neuroblastoma cells (CHP-134) and provided different effects in combination with the anti-GD2 antibody naxitamab. In particular, Nanofenretinide significantly increased the cytotoxic effect of naxitamab while Nanospermidine inhibited cell motility at extents proportional to naxitamab concentration. In neuroblastoma cells characterized by a low and heterogeneous basal expression of GD2, such as SH-SY5Y, which may represent the cell heterogeneity in tumors after chemotherapy, both Nanofenretinide and Nanospermidine increased GD2 expression in approximately 50% of cells, thus shifting the tumor population towards improved sensitivity to anti-GD2 antibodies.

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Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1

Cited by 29 publications

References 69 publications

Extracellular matrix topography drives adrenergic to mesenchymal transition in neuroblastoma

Extracellular matrix topography drives adrenergic to mesenchymal transition in neuroblastoma

Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit

Naxitamab Activity in Neuroblastoma Cells Is Enhanced by Nanofenretinide and Nanospermidine

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