Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation

Sinthu Pathmanapan; Raymond Poon; Tomasa Barrientos De Renshaw; Puviindran Nadesan; Makoto Nakagawa; Gireesh A. Seesankar; Adrian Kwan Ho Loe; Hongyuan H. Zhang; Joan J. Guinovart; Jordi Duran; Christopher B. Newgard; Jay S. Wunder; Benjamin A. Alman

doi:10.1016/j.celrep.2023.112578

Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation

Sinthu Pathmanapan, Raymond Poon, Tomasa Barrientos De Renshaw, Puviindran Nadesan, Makoto Nakagawa, Gireesh A. Seesankar, Adrian Kwan Ho Loe, Hongyuan H. Zhang, Joan J. Guinovart, Jordi Duran, Christopher B. Newgard, Jay S. Wunder, Benjamin A. Alman

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Resum

Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.

Idioma original	Anglès
Número d’article	112578
Nombre de pàgines	49
Revista	Cell Reports
Volum	42
Número	6
DOIs	https://doi.org/10.1016/j.celrep.2023.112578
Estat de la publicació	Publicada - 27 de juny 2023
Publicat externament	Sí

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10.1016/j.celrep.2023.112578Llicència: CC BY-NC-ND

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Pathmanapan, S., Poon, R., De Renshaw, T. B., Nadesan, P., Nakagawa, M., Seesankar, G. A., Ho Loe, A. K., Zhang, H. H., Guinovart, J. J., Duran, J., Newgard, C. B., Wunder, J. S., & Alman, B. A. (2023). Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation. Cell Reports, 42(6), Article 112578. https://doi.org/10.1016/j.celrep.2023.112578

@article{4b3397f9ef334607a6410932c2ed4056,

title = "Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation",

abstract = "Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.",

keywords = "cancer, chondrosarcoma, CP: Cancer, CP: Metabolism, development, genetic mutation, glycogen, metabolism, mutant IDH",

author = "Sinthu Pathmanapan and Raymond Poon and {De Renshaw}, {Tomasa Barrientos} and Puviindran Nadesan and Makoto Nakagawa and Seesankar, {Gireesh A.} and {Ho Loe}, {Adrian Kwan} and Zhang, {Hongyuan H.} and Guinovart, {Joan J.} and Jordi Duran and Newgard, {Christopher B.} and Wunder, {Jay S.} and Alman, {Benjamin A.}",

note = "Funding Information: We thank Dr. Qingxia Wei for generation of xenografts from patient chondrosarcoma tissues. We also thank Dr. Joan J Guinovart and Dr. Jordi Duran for Gys1 fl/fl mice shipment. We thank our funding sources, NIH R01 AR066765 and CIHR MOP-37913 , for funding this study. Publisher Copyright: {\textcopyright} 2023 The Authors.",

year = "2023",

month = jun,

day = "27",

doi = "10.1016/j.celrep.2023.112578",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

Pathmanapan, S, Poon, R, De Renshaw, TB, Nadesan, P, Nakagawa, M, Seesankar, GA, Ho Loe, AK, Zhang, HH, Guinovart, JJ, Duran, J, Newgard, CB, Wunder, JS & Alman, BA 2023, 'Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation', Cell Reports, vol. 42, núm. 6, 112578. https://doi.org/10.1016/j.celrep.2023.112578

TY - JOUR

T1 - Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation

AU - Pathmanapan, Sinthu

AU - Poon, Raymond

AU - De Renshaw, Tomasa Barrientos

AU - Nadesan, Puviindran

AU - Nakagawa, Makoto

AU - Seesankar, Gireesh A.

AU - Ho Loe, Adrian Kwan

AU - Zhang, Hongyuan H.

AU - Guinovart, Joan J.

AU - Duran, Jordi

AU - Newgard, Christopher B.

AU - Wunder, Jay S.

AU - Alman, Benjamin A.

N1 - Funding Information: We thank Dr. Qingxia Wei for generation of xenografts from patient chondrosarcoma tissues. We also thank Dr. Joan J Guinovart and Dr. Jordi Duran for Gys1 fl/fl mice shipment. We thank our funding sources, NIH R01 AR066765 and CIHR MOP-37913 , for funding this study. Publisher Copyright: © 2023 The Authors.

PY - 2023/6/27

Y1 - 2023/6/27

N2 - Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.

AB - Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.

KW - cancer

KW - chondrosarcoma

KW - CP: Cancer

KW - CP: Metabolism

KW - development

KW - genetic mutation

KW - glycogen

KW - metabolism

KW - mutant IDH

UR - http://www.scopus.com/inward/record.url?scp=85160799924&partnerID=8YFLogxK

UR - https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS&DestLinkType=FullRecord;KeyUT=001013479400001

U2 - 10.1016/j.celrep.2023.112578

DO - 10.1016/j.celrep.2023.112578

M3 - Article

AN - SCOPUS:85160799924

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 112578

ER -

Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation

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