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

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

In: NAT CANCER, Vol. 3, No. 8, 08.2022, p. 976-993.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Mabe, NW, Huang, M, Dalton, GN, Alexe, G, Schaefer, DA, Geraghty, AC, Robichaud, AL, Conway, AS, Khalid, D, Mader, MM, Belk, JA, Ross, KN, Sheffer, M, Linde, MH, Ly, N, Yao, W, Rotiroti, MC, Smith, BAH, Wernig, M, Bertozzi, CR, Monje, M, Mitsiades, CS, Majeti, R, Satpathy, AT, Stegmaier, K & Majzner, RG 2022, 'Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1', NAT CANCER, vol. 3, no. 8, pp. 976-993. https://doi.org/10.1038/s43018-022-00405-x

APA

Mabe, N. W., Huang, M., Dalton, G. N., Alexe, G., Schaefer, D. A., Geraghty, A. C., Robichaud, A. L., Conway, A. S., Khalid, D., Mader, M. M., Belk, J. A., Ross, K. N., Sheffer, M., Linde, M. H., Ly, N., Yao, W., Rotiroti, M. C., Smith, B. A. H., Wernig, M., ... Majzner, R. G. (2022). Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1. NAT CANCER, 3(8), 976-993. https://doi.org/10.1038/s43018-022-00405-x

Vancouver

Mabe NW, Huang M, Dalton GN, Alexe G, Schaefer DA, Geraghty AC et al. Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1. NAT CANCER. 2022 Aug;3(8):976-993. https://doi.org/10.1038/s43018-022-00405-x

Bibtex

@article{5580e296f7864dc3b1f04f6ed464035a,
title = "Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1",
abstract = "Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.",
keywords = "Antibodies, Monoclonal, Child, Gangliosides, Humans, Immunotherapy, Neoplasm Recurrence, Local/chemically induced, Neuroblastoma/drug therapy",
author = "Mabe, {Nathaniel W} and Min Huang and Dalton, {Guillermo N} and Gabriela Alexe and Schaefer, {Daniel A} and Geraghty, {Anna C} and Robichaud, {Amanda L} and Conway, {Amy S} and Delan Khalid and Mader, {Marius M} and Belk, {Julia A} and Ross, {Kenneth N} and Michal Sheffer and Linde, {Miles H} and Nghi Ly and Winnie Yao and Rotiroti, {Maria Caterina} and Smith, {Benjamin A H} and Marius Wernig and Bertozzi, {Carolyn R} and Michelle Monje and Mitsiades, {Constantine S} and Ravindra Majeti and Satpathy, {Ansuman T} and Kimberly Stegmaier and Majzner, {Robbie G}",
note = "{\textcopyright} 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = aug,
doi = "10.1038/s43018-022-00405-x",
language = "English",
volume = "3",
pages = "976--993",
journal = "NAT CANCER",
issn = "2662-1347",
publisher = "NATURE PUBLISHING GROUP",
number = "8",

}

RIS

TY - JOUR

T1 - Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1

AU - Mabe, Nathaniel W

AU - Huang, Min

AU - Dalton, Guillermo N

AU - Alexe, Gabriela

AU - Schaefer, Daniel A

AU - Geraghty, Anna C

AU - Robichaud, Amanda L

AU - Conway, Amy S

AU - Khalid, Delan

AU - Mader, Marius M

AU - Belk, Julia A

AU - Ross, Kenneth N

AU - Sheffer, Michal

AU - Linde, Miles H

AU - Ly, Nghi

AU - Yao, Winnie

AU - Rotiroti, Maria Caterina

AU - Smith, Benjamin A H

AU - Wernig, Marius

AU - Bertozzi, Carolyn R

AU - Monje, Michelle

AU - Mitsiades, Constantine S

AU - Majeti, Ravindra

AU - Satpathy, Ansuman T

AU - Stegmaier, Kimberly

AU - Majzner, Robbie G

N1 - © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/8

Y1 - 2022/8

N2 - Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.

AB - Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.

KW - Antibodies, Monoclonal

KW - Child

KW - Gangliosides

KW - Humans

KW - Immunotherapy

KW - Neoplasm Recurrence, Local/chemically induced

KW - Neuroblastoma/drug therapy

U2 - 10.1038/s43018-022-00405-x

DO - 10.1038/s43018-022-00405-x

M3 - SCORING: Journal article

C2 - 35817829

VL - 3

SP - 976

EP - 993

JO - NAT CANCER

JF - NAT CANCER

SN - 2662-1347

IS - 8

ER -