Metabolic heterogeneity confers differences in melanoma metastatic potential

Tasdogan, Alpaslan; Faubert, Brandon; Ramesh, Vijayashree; Ubellacker, Jessalyn M.; Shen, Bo; Solmonson, Ashley; Murphy, Malea M.; Gu, Zhimin; Gu, Wen; Martin, Misty; Kasitinon, Stacy Y.; Vandergriff, Travis; Mathews, Thomas P.; Zhao, Zhiyu; Schadendorf, Dirk; DeBerardinis, Ralph J.; Morrison, Sean J.

doi:10.1038/s41586-019-1847-2

Cited by 363 publications

(305 citation statements)

References 43 publications

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“…Indeed, lactate transporters inhibition reduces lactate uptake, induces a switch to glycolysis, and blocks metabolic symbiosis and tumor progression (80). Interestingly, higher levels of MCT1 confer a higher metastatic potential to melanoma cells as metastasizing cells depend on MCT1 to manage oxidative stress (81).…”

Section: Metabolic Heterogeneity In Tumorsmentioning

confidence: 99%

Metabolic Plasticity in Chemotherapy Resistance

et al. 2020

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Resistance of cancer cells to chemotherapy is the first cause of cancer-associated death. Thus, new strategies to deal with the evasion of drug response and to improve clinical outcomes are needed. Genetic and epigenetic mechanisms associated with uncontrolled cell growth result in metabolism reprogramming. Cancer cells enhance anabolic pathways and acquire the ability to use different carbon sources besides glucose. An oxygen and nutrient-poor tumor microenvironment determines metabolic interactions among normal cells, cancer cells and the immune system giving rise to metabolically heterogeneous tumors which will partially respond to metabolic therapy. Here we go into the best-known cancer metabolic profiles and discuss several studies that reported tumors sensitization to chemotherapy by modulating metabolic pathways. Uncovering metabolic dependencies across different chemotherapy treatments could help to rationalize the use of metabolic modulators to overcome therapy resistance.

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Section: Metabolic Heterogeneity In Tumorsmentioning

confidence: 99%

Metabolic Plasticity in Chemotherapy Resistance

et al. 2020

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“…AGC1 is an important mediator of the malate-aspartate shuttle, cytosolic aspartate levels, cytosolic NAD + /NADH ratio, and mitochondrial NADH levels (Alkan et al, 2018). Higher MCT1 expression and lactate consumption are correlated with efficient metastasis (Tasdogan et al, 2020). Reduced NAD + /NADH and pyruvate/lactate ratios in AGC1-KD cells (Alkan et al, 2018) may contribute to increased lactate uptake in vivo, leading to a similar metastatic phenotype reported in high MCT1-expressing cells.…”

Section: Discussionmentioning

confidence: 96%

Loss of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis

Alkan

Vesely

Hackl

et al. 2020

Preprint

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Background: Aspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo.However, the impact of aspartate synthesis on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malateaspartate shuttle, impairs cytosolic aspartate levels, NAD + /NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis.Results: AGC1 expression is positively correlated with worse patient prognosis in many cancers. AGC1knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells. Conclusion:This study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation do not always reflect the metastatic capacity in vivo.

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“…Metabolic heterogeneity has been described to result from (i) different mutations in the same tumor type 42 , (ii) the same driving oncogene in different tumor types 43 , (iii) the location of the same tumor cells when seeded at different sites in the body 40 , (iv) regional heterogeneity within the same tumors 44 , and (v) tumor stage (e.g. metastatic versus primary tumor cells) 45,46 . These comparisons illustrate the complexity of cancer metabolism.…”

Section: Discussionmentioning

confidence: 99%

Clonal Heterogeneity Supports Mitochondrial Metabolism in Pancreatic Cancer

Halbrook

Thurston

McCarthy

et al. 2020

Preprint

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Pancreatic ductal adenocarcinoma (PDA) is characterized by a heterogenous and densely fibrotic microenvironment. This limits functional vasculature and diffusion of nutrients through the tumor 1,2 . Accordingly, pancreatic cancer cells develop numerous metabolic adaptations to survive and proliferate in nutrient austere conditions 3-7 . Subtypes of PDA have been characterized by transcriptional and functional differences [8][9][10][11][12] , which have been reported to exist within the same tumor 13-15 . However, it remains unclear if this diversity extends to metabolic programming. Here, using a combination of metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses within neoplastic populations isolated from a single pancreatic tumor. Furthermore, these populations are poised for metabolic crosstalk, and in examining this, we find an unexpected role for asparagine in maintaining cell proliferation following mitochondrial inhibition. Functionally, when challenged by mitochondrial inhibition, asparagine supplementation increases intracellular levels of asparagine and aspartate, a rate limiting biosynthetic precursor [16][17][18] . Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes pancreatic tumors to mitochondrial targeting with phenformin. Together, these data extend the concept of metabolic diversity to neoplastic populations within individual tumors, while illustrating a new method of intratumoral communication that supports tumor fitness 19,20 . Finally, the combination of asparaginase with mitochondrial inhibition could provide a powerful new strategy for this difficult to treat disease. Introduction:The tumor microenvironment in pancreatic ductal adenocarcinoma (PDA) is a complex ecosystem 21 , with diverse populations of fibroblasts and immune cells functioning to create a niche supporting cancer cell survival and tumor growth 19,20,[22][23][24][25][26][27][28] . Accordingly, this allows for many and varied cooperative intratumoral crosstalk interactions in the microenvironment 29,30 . These extend to direct metabolic support of cancer cells from adjacent fibroblasts and tumor associated macrophages [31][32][33][34][35] .The majority of PDAs express mutant Kras, so early efforts to understand metabolism in pancreatic cancer focused on the cell intrinsic metabolic rewiring downstream of Kras signaling pathways [36][37][38] . In addition, extensive metabolic profiling of a large set of PDA cell lines revealed *

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Metabolic heterogeneity confers differences in melanoma metastatic potential

Cited by 363 publications

References 43 publications

Metabolic Plasticity in Chemotherapy Resistance

Metabolic Plasticity in Chemotherapy Resistance

Loss of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis

Clonal Heterogeneity Supports Mitochondrial Metabolism in Pancreatic Cancer

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