Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

Schild, Tanya; Low, Vivien; Blenis, John; Gomes, Ana P.

doi:10.1016/j.ccell.2018.02.001

Cited by 150 publications

(127 citation statements)

References 74 publications

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“…These data are consistent with recent evidence suggesting that cancer cells from disparate origins may converge to adopt similar metabolic phenotypes in a given organ. [54][55][56] In support of this hypothesis, we demonstrated that expression of catalytically active PHGDH in a non-brain trophic tumor cell line enables brain metastasis, while catalytically inactive PHGDH is far less efficient at promoting brain metastasis. Suppression of PHGDH decreases brain metastatic burden and improves the survival of mice with brain metastasis.…”

Section: Discussionsupporting

confidence: 58%

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

Ngo

Kim

Osorio-Vasquez

et al. 2020

Preprint

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A hallmark of metastasis is the adaptation of tumor cells to new environments. Although it is well established that the metabolic milieu of the brain is severely deprived of nutrients, particularly the amino acids serine and its catabolite glycine, how brain metastases rewire their metabolism to survive in the nutrient-limited environment of the brain is poorly understood. Here we demonstrate that cell-intrinsic de novo serine synthesis is a major determinant of brain metastasis. Whole proteome comparison of triple-negative breast cancer (TNBC) cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis and improved overall survival in mice, whereas expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Collectively, these findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain. Statement of SignificanceOur study highlights how limited serine and glycine availability within the brain microenvironment potentiates tumor cell sensitivity to serine synthesis inhibition. This finding underscores the importance of studying cancer metabolism in physiologically-relevant contexts, and provides a rationale for using PHGDH inhibitors to treat brain metastasis.

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Section: Discussionsupporting

confidence: 58%

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

Ngo

Kim

Osorio-Vasquez

et al. 2020

Preprint

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“…Therefore, it is extremely critical to explore novel therapeutic strategies for HCC . Unfortunately, until now, the molecular mechanisms driving HCC pathogenesis are still largely unclear . Further understood of the critical mechanisms would provide potential therapeutic strategies for HCC …”

Section: Introductionmentioning

confidence: 99%

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Wang

Guo

Nampoukime

et al. 2020

J Cellular Molecular Medi

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Hepatocellular carcinoma (HCC) is a main cause of cancer‐related deaths globally. Long non‐coding RNAs (lncRNAs) play important roles in diverse cancers. Our previous microarray‐based lncRNA profiling showed that LINC00467 was highly expressed in HCC. Here, we further explored the expression, role and functional mechanism of lncRNA LINC00467 in HCC. Our findings revealed that LINC00467 was up‐regulated in HCC tissues and HCC cell lines. Increased expression of LINC00467 was positively associated with tumour size and vascular invasion. In vitro functional experiments revealed that LINC00467 accelerated HCC cell proliferation, cell cycle progression and migration and reduced HCC cell apoptosis. In vivo functional assays revealed that LINC00467 drove HCC xenograft growth and HCC cell proliferation and repressed HCC cell apoptosis in vivo. Moreover, LINC00467 inhibited NR4A3 post‐transcriptionally via interacting with NR4A3 mRNA to form double‐stranded RNA, which was further degraded by Dicer. The expression of NR4A3 was inversely associated with LINC00467 in HCC tissues. Functional rescue assays found that restore of NR4A3 expression blocked the oncogenic roles of LINC00467 in HCC. Taken together, our results demonstrated that lncRNA LINC00467 was a novel highly expressed and oncogenic lncRNA in HCC via inhibiting NR4A3. Targeting LINC00467 or enhancing NR4A3 may be potential therapeutic strategies against HCC.

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“…37 Interestingly, circulating tumor cells (CTCs) reduce production of ROS to survive by switching towards a glycolytic metabolism and decreasing their aerobic respiration rate (oxidative phosphorylation). 38 In contrast, a recent molecular profiling study of malignant melanoma specimens derived from in vivo models and from a patient cohort with matched extracranial and brain metastasis revealed the importance of oxidative phosphorylation in brain metastases. 39 This indicates that during colonization of the brain, CTCs have to re-activate oxidative phosphorylation despite the associated increase in ROS production.…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, proliferation of metastatic cells pushes the metastatic daughter cells away from the vasculature, which leads to a decrease in oxygen supply and induction of hypoxia and a concomitant increase in ROS production . Interestingly, circulating tumor cells (CTCs) reduce production of ROS to survive by switching towards a glycolytic metabolism and decreasing their aerobic respiration rate (oxidative phosphorylation) . In contrast, a recent molecular profiling study of malignant melanoma specimens derived from in vivo models and from a patient cohort with matched extracranial and brain metastasis revealed the importance of oxidative phosphorylation in brain metastases .…”

Section: Discussionmentioning

confidence: 99%

LEF1 supports metastatic brain colonization by regulating glutathione metabolism and increasing ROS resistance in breast cancer

Blazquez

Rietkötter

Wenske

et al. 2019

Intl Journal of Cancer

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More than half of all brain metastases show infiltrating rather than displacing growth at the macro‐metastasis/organ parenchyma interface (MMPI), a finding associated with shorter survival. The lymphoid enhancer‐binding factor‐1 (LEF1) is an epithelial‐mesenchymal transition (EMT) transcription factor that is commonly overexpressed in brain‐colonizing cancer cells. Here, we overexpressed LEF1 in an in vivo breast cancer brain colonization model. It shortened survival, albeit without engaging EMT at the MMPI. By differential proteome analysis, we identified a novel function of LEF1 as a regulator of the glutathione (GSH) system, the principal cellular redox buffer. LEF1 overexpression also conferred resistance against therapeutic GSH depletion during brain colonization and improved management of intracellular ROS. We conclude that besides EMT, LEF1 facilitates metastasis by improving the antioxidative capacity of epithelial breast cancer cells, in particular during colonization of the brain parenchyma.

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Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

Cited by 150 publications

References 74 publications

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

LEF1 supports metastatic brain colonization by regulating glutathione metabolism and increasing ROS resistance in breast cancer

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