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 - 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 -