Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine

Yasaman Barekatain; Jeffrey J. Ackroyd; Victoria C. Yan; Sunada Khadka; Lin Wang; Ko Chien Chen; Anton H. Poral; Theresa Tran; Dimitra K. Georgiou; Kenisha Arthur; Yu Hsi Lin; Nikunj Satani; Elliot S. Ballato; Eliot I. Behr; Ana C. deCarvalho; Roel G.W. Verhaak; John de Groot; Jason T. Huse; John M. Asara; Raghu Kalluri; Florian L. Muller

doi:10.1038/s41467-021-24240-3

Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine

Yasaman Barekatain, Jeffrey J. Ackroyd, Victoria C. Yan, Sunada Khadka, Lin Wang, Ko Chien Chen, Anton H. Poral, Theresa Tran, Dimitra K. Georgiou, Kenisha Arthur, Yu Hsi Lin, Nikunj Satani, Elliot S. Ballato, Eliot I. Behr, Ana C. deCarvalho, Roel G.W. Verhaak, John de Groot, Jason T. Huse, John M. Asara, Raghu KalluriFlorian L. Muller

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21 Scopus citations

Abstract

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP’s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.

Original language	English (US)
Article number	4228
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24240-3
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Barekatain, Y., Ackroyd, J. J., Yan, V. C., Khadka, S., Wang, L., Chen, K. C., Poral, A. H., Tran, T., Georgiou, D. K., Arthur, K., Lin, Y. H., Satani, N., Ballato, E. S., Behr, E. I., deCarvalho, A. C., Verhaak, R. G. W., de Groot, J., Huse, J. T., Asara, J. M., ... Muller, F. L. (2021). Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine. Nature communications, 12(1), Article 4228. https://doi.org/10.1038/s41467-021-24240-3

Barekatain, Y, Ackroyd, JJ, Yan, VC, Khadka, S, Wang, L, Chen, KC, Poral, AH, Tran, T, Georgiou, DK, Arthur, K, Lin, YH, Satani, N, Ballato, ES, Behr, EI, deCarvalho, AC, Verhaak, RGW, de Groot, J, Huse, JT, Asara, JM, Kalluri, R & Muller, FL 2021, 'Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine', Nature communications, vol. 12, no. 1, 4228. https://doi.org/10.1038/s41467-021-24240-3

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title = "Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine",

abstract = "Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP{\textquoteright}s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.",

author = "Yasaman Barekatain and Ackroyd, {Jeffrey J.} and Yan, {Victoria C.} and Sunada Khadka and Lin Wang and Chen, {Ko Chien} and Poral, {Anton H.} and Theresa Tran and Georgiou, {Dimitra K.} and Kenisha Arthur and Lin, {Yu Hsi} and Nikunj Satani and Ballato, {Elliot S.} and Behr, {Eliot I.} and deCarvalho, {Ana C.} and Verhaak, {Roel G.W.} and {de Groot}, John and Huse, {Jason T.} and Asara, {John M.} and Raghu Kalluri and Muller, {Florian L.}",

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AU - Barekatain, Yasaman

AU - Ackroyd, Jeffrey J.

AU - Yan, Victoria C.

AU - Khadka, Sunada

AU - Wang, Lin

AU - Chen, Ko Chien

AU - Poral, Anton H.

AU - Tran, Theresa

AU - Georgiou, Dimitra K.

AU - Arthur, Kenisha

AU - Lin, Yu Hsi

AU - Satani, Nikunj

AU - Ballato, Elliot S.

AU - Behr, Eliot I.

AU - deCarvalho, Ana C.

AU - Verhaak, Roel G.W.

AU - de Groot, John

AU - Huse, Jason T.

AU - Asara, John M.

AU - Kalluri, Raghu

AU - Muller, Florian L.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP’s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.

AB - Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP’s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.

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Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine

Abstract

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