The Non-Essential Amino Acid Cysteine Becomes Essential for Tumor Proliferation and Survival

Combs, Joseph A.; DeNicola, Gina M.

doi:10.3390/cancers11050678

Cited by 218 publications

(175 citation statements)

References 134 publications

(227 reference statements)

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“…Cancer cells showed elevated dependence on multiple amino acids, including cysteine (Fig. 2B), glutamine, aspartate, asparagine and arginine [76][77][78] . Arginase breaks down arginine into urea and ornithine.…”

Section: Discussionmentioning

confidence: 99%

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Wang

Ruzzo

2020

Sci Rep

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Spatial heterogeneity is a fundamental feature of the tumor microenvironment (TME), and tackling spatial heterogeneity in neoplastic metabolic aberrations is critical for tumor treatment. Genomescale metabolic network models have been used successfully to simulate cancer metabolic networks. However, most models use bulk gene expression data of entire tumor biopsies, ignoring spatial heterogeneity in the TME. To account for spatial heterogeneity, we performed spatially-resolved metabolic network modeling of the prostate cancer microenvironment. We discovered novel malignantcell-specific metabolic vulnerabilities targetable by small molecule compounds. We predicted that inhibiting the fatty acid desaturase SCD1 may selectively kill cancer cells based on our discovery of spatial separation of fatty acid synthesis and desaturation. We also uncovered higher prostaglandin metabolic gene expression in the tumor, relative to the surrounding tissue. Therefore, we predicted that inhibiting the prostaglandin transporter SLCO2A1 may selectively kill cancer cells. Importantly, SCD1 and SLCO2A1 have been previously shown to be potently and selectively inhibited by compounds such as CAY10566 and suramin, respectively. We also uncovered cancer-selective metabolic liabilities in central carbon, amino acid, and lipid metabolism. Our novel cancer-specific predictions provide new opportunities to develop selective drug targets for prostate cancer and other cancers where spatial transcriptomics datasets are available.Cancer cells reprogram their metabolism to fulfill the energetic and biosynthetic needs of proliferation, invasion and migration 1 . This is exemplified in prostate cancer, the second most common cancer in American men after melanoma 2 . Previous studies have uncovered profound metabolic dysregulation in multiple pathways, particularly in fatty acid and lipid metabolism 3,4 . Discovering novel cancer-specific metabolic aberrations has significant translational applications, because cancer-associated metabolic dysfunctions can be exploited to advance cancer detection (e.g., 18 F-FDG (Fludeoxyglucose) imaging based on elevated glycolysis in cancer 5 ) and treatment (e.g., L-asparaginase in treating acute lymphoblastic leukemia 6 ).Cancer metabolic reprograming is profoundly impacted by spatial heterogeneity, a fundamental feature of the tumor microenvironment (TME) 7 . Heterogeneous distributions of blood vessels and stromal tissues create uneven spatial gradients of nutrients and metabolic byproducts, which significantly shape the phenotypes of many cell types in the TME 8 . Recent technologies, such as spatial transcriptomics 9,10 and Slide-seq 11 have enabled transcriptomic profiling of hundreds of locations within tissue sections with high spatial resolution (2-100 μm), and have been used to study multiple types of malignancies, including prostate cancer, breast cancer, pancreatic cancer, and melanoma 9,10,12-14 . These spatially-resolved datasets provide novel opportunities to dissect spatial metabolic heterogeneity i...

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Section: Discussionmentioning

confidence: 99%

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Wang

Ruzzo

2020

Sci Rep

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“…Moreover, immunotherapy was recently shown to sensitise to tumour cell ferroptosis (see Section 9). Considering that xCT is often aberrantly expressed in many cancers [125,126], ferroptosis induction may just prove to be a weak spot of cancer.…”

Section: Ferroptosis-inducing Therapy (Fit) For Cancer Treatmentmentioning

confidence: 99%

Ferroptosis in Cancer Cell Biology

Bebber

Müller

Clemente

et al. 2020

Cancers

263

209

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A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer.

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“…It is the main circulating form of cysteine that can be uptaken by cells. Cancer cells can become "addicted" to cysteine (283) and their reliance on cystine may be associated with EMT (284). Overexpression of miR-200c, that inhibits EMT, in cystine-addicted breast cancer cells resulted in these cells being less vulnerable to cystine deprivation (284).…”

Section: Amino Acid Metabolismmentioning

confidence: 99%

EMT Factors and Metabolic Pathways in Cancer

Georgakopoulos-Soares

et al. 2020

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The epithelial-mesenchymal transition (EMT) represents a biological program during which epithelial cells lose their cell identity and acquire a mesenchymal phenotype. EMT is normally observed during organismal development, wound healing and tissue fibrosis. However, this process can be hijacked by cancer cells and is often associated with resistance to apoptosis, acquisition of tissue invasiveness, cancer stem cell characteristics, and cancer treatment resistance. It is becoming evident that EMT is a complex, multifactorial spectrum, often involving episodic, transient or partial events. Multiple factors have been causally implicated in EMT including transcription factors (e.g., SNAIL, TWIST, ZEB), epigenetic modifications, microRNAs (e.g., miR-200 family) and more recently, long non-coding RNAs. However, the relevance of metabolic pathways in EMT is only recently being recognized. Importantly, alterations in key metabolic pathways affect cancer development and progression. In this review, we report the roles of key EMT factors and describe their interactions and interconnectedness. We introduce metabolic pathways that are involved in EMT, including glycolysis, the TCA cycle, lipid and amino acid metabolism, and characterize the relationship between EMT factors and cancer metabolism. Finally, we present therapeutic opportunities involving EMT, with particular focus on cancer metabolic pathways.

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The Non-Essential Amino Acid Cysteine Becomes Essential for Tumor Proliferation and Survival

Cited by 218 publications

References 134 publications

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Ferroptosis in Cancer Cell Biology

EMT Factors and Metabolic Pathways in Cancer

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