Metabolic features of cancer stem cells: the emerging role of lipid metabolism

Mancini, Rita; Noto, Alessia; Pisanu, Maria Elena; Vitis, Claudia De; Maugeri‐Saccà, Marcello; Ciliberto, Gennaro

doi:10.1038/s41388-018-0141-3

Cited by 114 publications

(113 citation statements)

References 122 publications

(158 reference statements)

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“…Since CSCs are very plastic, several studies proposed a glycolytic associated phenotype of CSCs, whereas other findings suggested a prevalent mitochondrial oxidative metabolism (reviewed Concordantly, SCD1 activation and consequent MUFA production seems to be a probable CSC hallmark. 116 Notably, peculiar alterations of CSC-iron trafficking can sustain their role in cancer growth. It has been shown that CSCs of different types of tumours are iron-rich in comparison with tumour cells.…”

Section: Cancer Stem Cell Metabolismmentioning

confidence: 99%

Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma

Vicent

Lieshout

Verstegen

et al. 2019

Liver International

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Human cholangiocarcinoma (CCA) is an aggressive tumour entity arising from the biliary tree, whose molecular pathogenesis remains largely undeciphered. Over the last decade, the advent of high‐throughput and cell‐based techniques has significantly increased our knowledge on the molecular mechanisms underlying this disease while, at the same time, unravelling CCA complexity. In particular, it becomes clear that CCA displays pronounced inter‐ and intratumoural heterogeneity, which is presumably the consequence of the interplay between distinct tissues and cells of origin, the underlying diseases, and the associated molecular alterations. To better characterize these events and to design novel and more effective therapeutic strategies, a number of CCA experimental and preclinical models have been developed and are currently generated. This review summarizes the current knowledge and understanding of these models, critically underlining their translational usefulness and limitations. Furthermore, this review aims to provide a comprehensive overview on cells of origin, cancers stem cells and their dynamic interplay within CCA tissue.

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Section: Cancer Stem Cell Metabolismmentioning

confidence: 99%

Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma

Vicent

Lieshout

Verstegen

et al. 2019

Liver International

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“…Perturbations in lipid metabolism are emerging as potential drivers and therapeutic targets in cancer development and progression [7]. This is of particular relevance because obesity is a risk factor for a number of cancer types, including multiple myeloma (MM) [1].…”

Section: Introductionmentioning

confidence: 99%

Concurrent lipidomics and proteomics on malignant plasma cells from multiple myeloma patients: Probing the lipid metabolome

Mohamed

Collins

Jiang

et al. 2019

Preprint

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17Background: Multiple myeloma (MM) is a hematological malignancy characterized by the 18 clonal expansion of malignant plasma cells. Though durable remissions are possible, MM is 19 considered incurable, with relapse occurring in almost all patients. There has been limited 20 data reported on the lipid metabolism changes in plasma cells during MM progression. Here, 21we evaluated the feasibility of concurrent lipidomics and proteomics analyses from patient 22 plasma cells, and report these data on a limited number of patient samples, demonstrating the 23 feasibility of the method, and establishing hypotheses to be evaluated in the future. 24Methods: Plasma cells were purified from fresh bone marrow aspirates using CD138 25 microbeads. Proteins and lipids were extracted using a bi-phasic solvent system with 26 methanol, methyl tert-butyl ether, and water. Untargeted proteomics, untargeted and targeted 27 lipidomics were performed on 7 patient samples using liquid chromatography-mass 28 spectrometry. Two comparisons were conducted: high versus low risk; relapse versus newly 29 diagnosed. Proteins and pathways enriched in the relapsed group was compared to a public 30 transcriptomic dataset from Multiple Myeloma Research Consortium reference collection 31 (n=222) at gene and pathways level. 32Results: From one million purified plasma cells, we were able to extract material and 33 complete untargeted (~6000 and ~3600 features in positive and negative mode respectively) 34 and targeted lipidomics (313 lipids), as well as untargeted proteomics analysis (~4100 35 reviewed proteins). Comparative analyses revealed limited differences between high and low 36 risk groups (according to the standard clinical criteria), hence we focused on drawing 37 comparisons between the relapsed and newly diagnosed patients. Untargeted and targeted 38 lipidomics indicated significant down-regulation of phosphatidylcholines (PCs) in relapsed 39 MM. Although there was limited overlap of the differential proteins/transcripts, 76 40 Page 3 of 29 significantly enriched pathways in relapsed MM were common between proteomics and 41 transcriptomics data. Further evaluation of transcriptomics data for lipid metabolism network 42 revealed enriched correlation of PC, ceramide, cardiolipin, arachidonic acid and cholesterol 43 metabolism pathways to be exclusively correlated among relapsed but not in newly-44 diagnosed patients. 45 Conclusions:This study establishes the feasibility and workflow to conduct integrated 46 lipidomics and proteomics analyses on patient-derived plasma cells. Potential lipid 47 metabolism changes associated with MM relapse warrant further investigation. 48

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“…Besides the needs of MUFAs for the synthesis of complex lipids such as diacyglycerols (DG), triglycerides (TGs) and cholesterol esters, MUFAs also have important functions in cell signaling and membrane fluidity (11). Therefore, SCD is a highly regulated and conserved enzyme that plays important roles in regulating obesity, insulin resistance, inflammation and cancer progression (12,13). Humans have two SCD isoforms (SCD1 and SCD5), while mouse has four (SCD1-4) that share homology with human SCD1, but not human SCD5 (14,15).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Stearoyl-CoA desaturase suppresses follicular help T and germinal center B cell responses

Son

Cheon

Goplen

et al. 2019

Preprint

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25Stearoyl-CoA desaturases (SCD) are endoplasmic reticulum (ER) associated enzymes that 26 catalyze the synthesis of the monounsaturated fatty acids (MUFAs). As such, SCD play important 27 roles in maintaining the intracellular balance between saturated fatty acid (SFAs) and MUFAs. 28 The roles of SCD in CD4 + T helper cell responses are currently unexplored. Here, we have found 29 that murine and human follicular helper T (T FH ) cells express higher levels of SCD1 compared to 30 non-T FH cells. Further, the expression of SCD1 in T FH cells is dependent on the T FH lineage-31 specification transcription factor BCL6. We found that the inhibition of SCD1 impaired T FH cell 32 maintenance and shifted the balance between T FH and follicular regulatory T (T FR ) cells in the 33 spleen. Consequently, SCD1 inhibition dampened germinal center B cell responses following 34 influenza immunization. Mechanistically, we found that SCD inhibition led to increased ER stress 35 and enhanced T FH cell apoptosis in vitro and in vivo. These results reveal a possible link between 36 fatty acid metabolism and cellular and humoral responses induced by immunization or potentially, 37 autoimmunity. 38 39 40 41 42 43 44 45 46 47 48formation of germinal centers (GCs) and the production of class-switched high-affinity 53 immunoglobulins (1). T FH cells are required for the generation of antibody-mediated protection 54 against microbes, but aberrant T FH responses may cause autoimmunity (2). Therefore, it is 55 important to understand the positive and/or negative regulators of T FH cell responses for the proper 56 induction during vaccination or the inhibition of T FH responses during autoimmunity. 57T FH differentiation in vivo is a multifactorial multistep process. The transcription factor BCL-6 is 58 considered the master regulator for the differentiation of T FH cells and subsequent germinal center 59 responses (3,4). Interestingly, recent evidence suggests that cell metabolic processes may play 60 important roles in modulating T FH development in vivo. BCL6 was shown to repress glycolysis 61 promoting BCL6 expression in activated CD4 T cells (5,6). Consistent with those observations, it 62 has been demonstrated that T FH cells exhibit diminished glycolysis and mitochondrial respiration 63 compared to Th1 cells. However, a recent study has also suggested mTOR kinase complex 1 64 (mTORC1) related glucose metabolism is required for the T FH generation in vivo (7). Therefore, 65 the roles of glucose metabolism in negative and positive regulation of T FH differentiation and/or 66 maintenance remain to be elucidated. 67Besides glucose metabolism, emerging evidence has suggested that lipid metabolism also plays 68 important roles in regulating T helper cell responses. The inhibition of acetyl-CoA carboxylase 1 69 (ACC1), a key substrate for fatty acid synthesis, reduces human and mouse Th17 cell development 70 in favor of regulatory T (Treg) cell differentiation (8). Simvastatin, the inhibitors for 3-hydroxy-71 3-methyglutaryl (HMG)...

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Metabolic features of cancer stem cells: the emerging role of lipid metabolism

Cited by 114 publications

References 122 publications

Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma

Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma

Concurrent lipidomics and proteomics on malignant plasma cells from multiple myeloma patients: Probing the lipid metabolome

Inhibition of Stearoyl-CoA desaturase suppresses follicular help T and germinal center B cell responses

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