TY - JOUR
T1 - Elevated endogenous SDHA drives pathological metabolism in highly metastatic uveal melanoma
AU - Chattopadhyay, Chandrani
AU - Oba, Junna
AU - Roszik, Jason
AU - Marszalek, Joseph R.
AU - Chen, Ken
AU - Qi, Yuan
AU - Eterovic, Karina
AU - Gordon Robertson, A.
AU - Burks, Jared K.
AU - McCannel, Tara A.
AU - Grimm, Elizabeth A.
AU - Woodman, Scott E.
N1 - Funding Information:
Supported by Miriam and Sheldon Adelson AMRF (CC, JR, EAG), MELANOMA SPORE MDACC (CC, EAG, SEW), MDACC Melanoma Moonshot (SEW, JO), Melanoma Research Alliance Young Investigator Award, University of Texas System Rising Star Award, NCI SPORE in Melanoma (P50 CA093459) Developmental Research Project Award, NIH/NCI Cancer Center Support Grant P30 CA016672 Faculty Award (SEW), the George E. and Ruth Moss Trust, Cancer Prevention and Research Institute of Texas (SEW, JO), and an unrestricted grant from Research to Prevent Blindness (TMC).
Funding Information:
The authors thank Marina Protopopova for help with Seahorse Analysis, the Flow Cytometry and Cellular Imaging Facility for assistance with mitotracker imaging, and Jennifer McGee for her expert graphical design work. Supported by Miriam and Sheldon Adelson AMRF (CC, JR, EAG), MELANOMA SPORE MDACC (CC, EAG, SEW), MDACC Melanoma Moonshot (SEW, JO), Melanoma Research Alliance Young Investigator Award, University of Texas System Rising Star Award, NCI SPORE in Melanoma (P50 CA093459) Developmental Research Project Award, NIH/NCI Cancer Center Support Grant P30 CA016672 Faculty Award (SEW), the George E. and Ruth Moss Trust, Cancer Prevention and Research Institute of Texas (SEW, JO), and an unrestricted grant from Research to Prevent Blindness (TMC).
Publisher Copyright:
Copyright 2019 The Authors
PY - 2019/10/1
Y1 - 2019/10/1
N2 - PURPOSE. Metastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy. Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy. METHODS. We assessed two sets of oxidative phosphorylation (OxPhos) genes within 9858 tumors across 31 cancer types. An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non-M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition. RESULTS. We identified UM to have among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the tricarboxylic acid cycle with OxPhos by oxidizing (lowering) succinate. We showed that SDHA-high M3 UM have elevated expression of key OxPhos molecules, exhibit abundant mitochondrial reserve respiratory capacity, and are resistant to OxPhos antagonism, which can be reversed by SDHA knockdown. CONCLUSIONS. Our study has identified a critical metabolic program within poor prognostic M3 UM. In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediate resistance to therapy that is reversible with targeted treatment.
AB - PURPOSE. Metastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy. Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy. METHODS. We assessed two sets of oxidative phosphorylation (OxPhos) genes within 9858 tumors across 31 cancer types. An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non-M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition. RESULTS. We identified UM to have among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the tricarboxylic acid cycle with OxPhos by oxidizing (lowering) succinate. We showed that SDHA-high M3 UM have elevated expression of key OxPhos molecules, exhibit abundant mitochondrial reserve respiratory capacity, and are resistant to OxPhos antagonism, which can be reversed by SDHA knockdown. CONCLUSIONS. Our study has identified a critical metabolic program within poor prognostic M3 UM. In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediate resistance to therapy that is reversible with targeted treatment.
KW - Mitochondrial metabolism
KW - Monosomy 3
KW - OxPhos
KW - SDHA
KW - Uveal melanoma
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U2 - 10.1167/iovs.19-28082
DO - 10.1167/iovs.19-28082
M3 - Article
C2 - 31596927
AN - SCOPUS:85073110800
SN - 0146-0404
VL - 60
SP - 4187
EP - 4195
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 13
ER -