TY - JOUR
T1 - A Short Isoform of Spermatogenic Enzyme GAPDHS Functions as a Metabolic Switch and Limits Metastasis in Melanoma
AU - Gill, Jennifer G.
AU - Leef, Samantha N.
AU - Ramesh, Vijayashree
AU - Martin-Sandoval, Misty S.
AU - Rao, Aparna D.
AU - West, Lindsey
AU - Muh, Sarah
AU - Gu, Wen
AU - Zhao, Zhiyu
AU - Hosler, Gregory A.
AU - Vandergriff, Travis W.
AU - Durham, Alison B.
AU - Mathews, Thomas P.
AU - Aurora, Arin B.
N1 - Funding Information:
J.G. Gill reports grants from Cancer Prevention and Research Institute of Texas, Dermatology Foundation, and NIH during the conduct of the study. S. Muh reports grants from Cancer Prevention and Research Institute of Texas during the conduct of the study. T. Mathews reports grants from Cancer Prevention and Research Institute of Texas during the conduct of the study. A.B. Aurora reports grants from Cancer Prevention and Research Institute of Texas during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
The research was supported by the Cancer Prevention and Research Institute of Texas (MIRA RP180778 to J.G. Gill, S.N. Leef, V. Ramesh, M.S. Martin-Sandoval, Z. Zhao, and T.P. Mathews, and A.B. Aurora) and the NIH (UL1TR002240 to A.B. Durham). J.G. Gill was supported by the Dermatology Foundation and the NIH (T32 AR065969). A.D. Rao was supported by the Victorian Cancer Agency. A.B. Durham was supported by the NIH Clinical and Translational Science Awards Program (UL1TR002240). The authors thank S.J. Morrison for the generous use of his laboratory’s resources as well as helpful conversations and guidance. They thank M. Nitcher for mouse colony management as well as N. Loof and the Moody Foundation Flow Cytometry Facility. The authors thank A. Tasdogan and B. Faubert for assistance in metabolic protocols. They thank V. Khivansara for help in RNA-seq
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Despite being the leading cause of cancer deaths, metastasis remains a poorly understood process. To identify novel regulators of metastasis in melanoma, we performed a large-scale RNA sequencing screen of 48 samples from patient-derived xenograft (PDX) subcutaneous melanomas and their associated metastases. In comparison with primary tumors, expression of glycolytic genes was frequently decreased in metastases, whereas expression of some tricarboxylic acid (TCA) cycle genes was increased in metastases. Consistent with these transcriptional changes, melanoma metastases underwent a metabolic switch characterized by decreased levels of glycolytic metabolites and increased abundance of TCA cycle metabolites. A short isoform of glyceraldehyde- 3-phosphate dehydrogenase, spermatogenic (GAPDHS) lacking the N-terminal domain suppressed metastasis and regulated this metabolic switch. GAPDHS was downregulated in metastatic nodules from PDX models as well as in human patients. Overexpression of GAPDHS was sufficient to block melanoma metastasis, whereas its inhibition promoted metastasis, decreased glycolysis, and increased levels of certain TCA cycle metabolites and their derivatives including citrate, fumarate, malate, and aspartate. Isotope tracing studies indicated that GAPDHS mediates this shift through changes in pyruvate carboxylase activity and aspartate synthesis, both metabolic pathways critical for cancer survival and metastasis. Together, these data identify a short isoform of GAPDHS that limits melanoma metastasis and regulates central carbon metabolism.
AB - Despite being the leading cause of cancer deaths, metastasis remains a poorly understood process. To identify novel regulators of metastasis in melanoma, we performed a large-scale RNA sequencing screen of 48 samples from patient-derived xenograft (PDX) subcutaneous melanomas and their associated metastases. In comparison with primary tumors, expression of glycolytic genes was frequently decreased in metastases, whereas expression of some tricarboxylic acid (TCA) cycle genes was increased in metastases. Consistent with these transcriptional changes, melanoma metastases underwent a metabolic switch characterized by decreased levels of glycolytic metabolites and increased abundance of TCA cycle metabolites. A short isoform of glyceraldehyde- 3-phosphate dehydrogenase, spermatogenic (GAPDHS) lacking the N-terminal domain suppressed metastasis and regulated this metabolic switch. GAPDHS was downregulated in metastatic nodules from PDX models as well as in human patients. Overexpression of GAPDHS was sufficient to block melanoma metastasis, whereas its inhibition promoted metastasis, decreased glycolysis, and increased levels of certain TCA cycle metabolites and their derivatives including citrate, fumarate, malate, and aspartate. Isotope tracing studies indicated that GAPDHS mediates this shift through changes in pyruvate carboxylase activity and aspartate synthesis, both metabolic pathways critical for cancer survival and metastasis. Together, these data identify a short isoform of GAPDHS that limits melanoma metastasis and regulates central carbon metabolism.
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U2 - 10.1158/0008-5472.CAN-21-2062
DO - 10.1158/0008-5472.CAN-21-2062
M3 - Article
C2 - 35149585
AN - SCOPUS:85128118335
SN - 0008-5472
VL - 82
SP - 1251
EP - 1266
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -