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Article: Metabolite-derived protein modifications modulating oncogenic signaling.

Liu, Yawen / Vandekeere, Anke / Xu, Min / Fendt, Sarah-Maria / Altea-Manzano, Patricia

2022 Volume 12, Page(s) 988626

Abstract: Malignant growth is defined by multiple aberrant cellular features, including metabolic rewiring, inactivation of tumor suppressors and the activation of oncogenes. Even though these features have been described as separate hallmarks, many studies have ... ...

Abstract	Malignant growth is defined by multiple aberrant cellular features, including metabolic rewiring, inactivation of tumor suppressors and the activation of oncogenes. Even though these features have been described as separate hallmarks, many studies have shown an extensive mutual regulatory relationship amongst them. On one hand, the change in expression or activity of tumor suppressors and oncogenes has extensive direct and indirect effects on cellular metabolism, activating metabolic pathways required for malignant growth. On the other hand, the tumor microenvironment and tumor intrinsic metabolic alterations result in changes in intracellular metabolite levels, which directly modulate the protein modification of oncogenes and tumor suppressors at both epigenetic and post-translational levels. In this mini-review, we summarize the crosstalk between tumor suppressors/oncogenes and metabolism-induced protein modifications at both levels and explore the impact of metabolic (micro)environments in shaping these.
Language	English
Publishing date	2022-09-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.988626
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Article ; Online: Loss of attachment promotes proline accumulation and excretion in cancer cells.

Pilley, Steven E / Hennequart, Marc / Vandekeere, Anke / Blagih, Julianna / Legrave, Nathalie M / Fendt, Sarah-Maria / Vousden, Karen H / Labuschagne, Christiaan F

Science advances

2023 Volume 9, Issue 36, Page(s) eadh2023

Abstract: Previous studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to loss of attachment by accumulating and secreting proline. Detached cells display ... ...

Abstract	Previous studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to loss of attachment by accumulating and secreting proline. Detached cells display reduced proliferation accompanied by a general decrease in overall protein production and de novo amino acid synthesis compared to attached cells. However, proline synthesis was maintained under detached conditions. Furthermore, while overall proline incorporation into proteins was lower in detached cells compared to other amino acids, there was an increased production of the proline-rich protein collagen. The increased excretion of proline from detached cells was also shown to be used by macrophages, an abundant and important component of the tumor microenvironment. Our study suggests that detachment induced accumulation and secretion of proline may contribute to tumor progression by supporting increased production of extracellular matrix and providing proline to surrounding stromal cells.
MeSH term(s)	Proline ; Amino Acids ; Biological Transport ; Extracellular Matrix ; Macrophages ; Neoplasms
Chemical Substances	Proline (9DLQ4CIU6V) ; Amino Acids
Language	English
Publishing date	2023-09-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adh2023
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Article ; Online: Aging-accumulated methylmalonic acid serum levels at breast cancer diagnosis are not associated with distant metastases.

Wu, Qi / Hatse, Sigrid / Kenis, Cindy / Fernández-García, Juan / Altea-Manzano, Patricia / Billen, Jaak / Planque, Mélanie / Vandekeere, Anke / Lambrechts, Yentl / Richard, François / Punie, Kevin / Neven, Patrick / Smeets, Ann / Nevelsteen, Ines / Floris, Giuseppe / Desmedt, Christine / Gomes, Ana P / Fendt, Sarah-Maria / Wildiers, Hans

Breast cancer research and treatment

2024

Abstract: Purpose: Recent evidence suggests that age-accumulated methylmalonic acid (MMA) promotes breast cancer progression in mice. This study aims to investigate the association between baseline serum MMA concentrations in patients with breast cancer and the ... ...

Abstract	Purpose: Recent evidence suggests that age-accumulated methylmalonic acid (MMA) promotes breast cancer progression in mice. This study aims to investigate the association between baseline serum MMA concentrations in patients with breast cancer and the development of subsequent distant metastases. Methods: We included 32 patients with early Luminal B-like breast cancer (LumB, median age 62.4y) and 52 patients with early triple-negative breast cancer (TNBC, median age 50.5y) who developed distant metastases within 5 years. They were matched to an equal number of early breast cancer patients (median age 62.2y for LumB and 50.5y for TNBC) who did not develop distant metastases with at least 5 years of follow-up. Results: Baseline serum MMA levels at breast cancer diagnosis showed a positive correlation with age (P < 0.001) and a negative correlation with renal function and vitamin B12 (all P < 0.02), but no statistical association was found with BMI or tumor stage (P > 0.6). Between matched pairs, no significant difference was observed in MMA levels, after adjusting for kidney function and age (P = 0.19). Additionally, in a mouse model, a significant decline in MMA levels was observed in the tumor-bearing group compared to the group without tumors before and after tumor establishment or at identical times for the control group (P = 0.03). Conclusion: Baseline serum MMA levels in patients with breast cancer are not correlated with secondary distant metastasis. Evidence in the mouse model suggests that the presence of a tumor perturbates MMA levels.
Language	English
Publishing date	2024-03-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-024-07260-7
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Zs.A 1655: Show issues

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Article ; Online: HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.

Urrutia, Andrés A / Mesa-Ciller, Claudia / Guajardo-Grence, Andrea / Alkan, H Furkan / Soro-Arnáiz, Inés / Vandekeere, Anke / Ferreira Campos, Ana Margarida / Igelmann, Sebastian / Fernández-Arroyo, Lucía / Rinaldi, Gianmarco / Lorendeau, Doriane / De Bock, Katrien / Fendt, Sarah-Maria / Aragonés, Julián

Cell reports

2024 Volume 43, Issue 4, Page(s) 114103

Abstract: Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous ... ...

Abstract	Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD
MeSH term(s)	Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Glycolysis ; Cell Proliferation ; NAD/metabolism ; Cell Line, Tumor ; Mitochondria/metabolism ; Animals ; Pyruvic Acid/metabolism ; Lactic Acid/metabolism ; Neoplasms/metabolism ; Neoplasms/pathology ; Mice
Chemical Substances	Hypoxia-Inducible Factor 1, alpha Subunit ; NAD (0U46U6E8UK) ; HIF1A protein, human ; Pyruvic Acid (8558G7RUTR) ; Lactic Acid (33X04XA5AT)
Language	English
Publishing date	2024-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2024.114103
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Article ; Online: Diet-induced loss of adipose hexokinase 2 correlates with hyperglycemia.

Shimobayashi, Mitsugu / Thomas, Amandine / Shetty, Sunil / Frei, Irina C / Wölnerhanssen, Bettina K / Weissenberger, Diana / Vandekeere, Anke / Planque, Mélanie / Dietz, Nikolaus / Ritz, Danilo / Meyer-Gerspach, Anne Christin / Maier, Timm / Hay, Nissim / Peterli, Ralph / Fendt, Sarah-Maria / Rohner, Nicolas / Hall, Michael N

eLife

2023 Volume 12

Abstract: Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of ... ...

Abstract	Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of
MeSH term(s)	Animals ; Mice ; Hexokinase/genetics ; Hexokinase/metabolism ; Obesity/metabolism ; Hyperglycemia/metabolism ; Insulin Resistance ; Glucose/metabolism ; Adipose Tissue/metabolism ; Diet, High-Fat ; Mice, Inbred C57BL
Chemical Substances	Hexokinase (EC 2.7.1.1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2023-03-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.85103
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Article ; Online: Serum methylmalonic acid concentrations at breast cancer diagnosis significantly correlate with clinical frailty.

GeroScience

2023 Volume 46, Issue 2, Page(s) 1489–1498

Abstract: Methylmalonic acid (MMA), a by-product of propionate metabolism, is known to increase with age. This study investigates the potential of serum MMA concentrations as a biomarker for age-related clinical frailty in older patients with breast cancer. One ... ...

Abstract	Methylmalonic acid (MMA), a by-product of propionate metabolism, is known to increase with age. This study investigates the potential of serum MMA concentrations as a biomarker for age-related clinical frailty in older patients with breast cancer. One hundred nineteen patients ≥ 70 years old with early-stage breast cancer were included (median age 76 years). G8 screening, full geriatric assessment, clinical parameters (i.e., estimated glomerular filtration rate (eGFR) and body mass index (BMI)), and serum sample collection were collected at breast cancer diagnosis before any therapy was administered. MMA concentrations were measured via liquid chromatography with tandem mass spectrometry. MMA concentrations significantly increased with age and eGFR (all P < 0.001) in this older population. The group with an abnormal G8 (≤ 14, 51% of patients) had significantly higher MMA levels than the group with normal G8 (> 14, 49%): 260 nmol/L vs. 188 nmol/L, respectively (P = 0.0004), even after correcting for age and eGFR (P = 0.001). Furthermore, in the detailed assessment, MMA concentrations correlated most with mobility (Eastern Cooperative Oncology Group (ECOG) Performance Status and Activities of Daily Living (ADL) tools, all P ≤ 0.02), comorbidity (Charlson Comorbidity Index (CCI) tool, P = 0.005), and polypharmacy (P < 0.001), whereas no significant associations were noted for instrumental ADL (IADL), Mini-Mental State Examination (MMSE), Geriatric Depression Scale-15 (GDS15), Mini Nutritional Assessment-Short Form (MNA-SF), and pain (all P > 0.1). In addition, our results showed that higher MMA levels correlate with poor overall survival in breast cancer patients (P = 0.003). Elevated serum MMA concentrations at initial diagnosis are significantly associated, not only with age but also independently with clinical frailty, suggesting a possible influence of MMA on clinical frailty in older patients with early-stage breast cancer.
MeSH term(s)	Humans ; Aged ; Female ; Frailty/diagnosis ; Frailty/complications ; Breast Neoplasms/diagnosis ; Methylmalonic Acid ; Activities of Daily Living ; Comorbidity
Chemical Substances	Methylmalonic Acid (8LL8S712J7)
Language	English
Publishing date	2023-08-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-023-00908-0
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Zs.A 1502: Show issues

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Article ; Online: In crystallo

Christensen, Emily M / Bogner, Alexandra N / Vandekeere, Anke / Tam, Gabriela S / Patel, Sagar M / Becker, Donald F / Fendt, Sarah-Maria / Tanner, John J

The Journal of biological chemistry

2020 Volume 295, Issue 52, Page(s) 18316–18327

Abstract: Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing ... ...

Abstract	Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing Δ
MeSH term(s)	Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Catalytic Domain ; Crystallography, X-Ray ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Phenotype ; Proline/analogs & derivatives ; Pyrroline Carboxylate Reductases/antagonists & inhibitors ; Pyrroline Carboxylate Reductases/metabolism ; Tumor Cells, Cultured ; delta-1-Pyrroline-5-Carboxylate Reductase
Chemical Substances	Enzyme Inhibitors ; Proline (9DLQ4CIU6V) ; Pyrroline Carboxylate Reductases (EC 1.5.1.-)
Language	English
Publishing date	2020-10-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA120.016106
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Uc I Zs.108: Show issues

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Article ; Online: Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.

Altea-Manzano, Patricia / Vandekeere, Anke / Edwards-Hicks, Joy / Roldan, Mar / Abraham, Emily / Lleshi, Xhordi / Guerrieri, Ania Naila / Berardi, Domenica / Wills, Jimi / Junior, Jair Marques / Pantazi, Asimina / Acosta, Juan Carlos / Sanchez-Martin, Rosario M / Fendt, Sarah-Maria / Martin-Hernandez, Miguel / Finch, Andrew J

Molecular cell

2022 Volume 82, Issue 23, Page(s) 4537–4547.e7

Abstract: Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial ... ...

Abstract	Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD
MeSH term(s)	NAD/metabolism ; Malate Dehydrogenase/genetics ; Malate Dehydrogenase/metabolism ; Oxidation-Reduction ; Citric Acid Cycle/physiology ; Respiration
Chemical Substances	NAD (0U46U6E8UK) ; Malate Dehydrogenase (EC 1.1.1.37)
Language	English
Publishing date	2022-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.10.005
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Zs.A 5055: Show issues

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Article ; Online: Mitochondria metabolism sets the species-specific tempo of neuronal development.

Iwata, Ryohei / Casimir, Pierre / Erkol, Emir / Boubakar, Leïla / Planque, Mélanie / Gallego López, Isabel M / Ditkowska, Martyna / Gaspariunaite, Vaiva / Beckers, Sofie / Remans, Daan / Vints, Katlijn / Vandekeere, Anke / Poovathingal, Suresh / Bird, Matthew / Vlaeminck, Ine / Creemers, Eline / Wierda, Keimpe / Corthout, Nikky / Vermeersch, Pieter /

Carpentier, Sébastien / Davie, Kristofer / Mazzone, Massimiliano / Gounko, Natalia V / Aerts, Stein / Ghesquière, Bart / Fendt, Sarah-Maria / Vanderhaeghen, Pierre

Science (New York, N.Y.)

2023 Volume 379, Issue 6632, Page(s) eabn4705

Abstract: Neuronal development in the human cerebral cortex is considerably prolonged compared with that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical ... ...

Abstract	Neuronal development in the human cerebral cortex is considerably prolonged compared with that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny.
MeSH term(s)	Animals ; Humans ; Mice ; Cerebral Cortex/cytology ; Cerebral Cortex/growth & development ; Energy Metabolism ; Mitochondria/metabolism ; Neurogenesis ; Neurons/metabolism
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abn4705
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Zs.A 27: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 77: Show issues

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Article ; Online: mTOR Signaling and SREBP Activity Increase FADS2 Expression and Can Activate Sapienate Biosynthesis.

Triki, Mouna / Rinaldi, Gianmarco / Planque, Melanie / Broekaert, Dorien / Winkelkotte, Alina M / Maier, Carina R / Janaki Raman, Sudha / Vandekeere, Anke / Van Elsen, Joke / Orth, Martin F / Grünewald, Thomas G P / Schulze, Almut / Fendt, Sarah-Maria

Cell reports

2020 Volume 31, Issue 12, Page(s) 107806

Abstract: Cancer cells display an increased plasticity in their lipid metabolism, which includes the conversion of palmitate to sapienate via the enzyme fatty acid desaturase 2 (FADS2). We find that FADS2 expression correlates with mammalian target of rapamycin ( ... ...

Abstract	Cancer cells display an increased plasticity in their lipid metabolism, which includes the conversion of palmitate to sapienate via the enzyme fatty acid desaturase 2 (FADS2). We find that FADS2 expression correlates with mammalian target of rapamycin (mTOR) signaling and sterol regulatory element-binding protein 1 (SREBP-1) activity across multiple cancer types and is prognostic in some cancer types. Accordingly, activating mTOR signaling by deleting tuberous sclerosis complex 2 (Tsc2) or overexpression of SREBP-1/2 is sufficient to increase FADS2 mRNA expression and sapienate metabolism in mouse embryonic fibroblasts (MEFs) and U87 glioblastoma cells, respectively. Conversely, inhibiting mTOR signaling decreases FADS2 expression and sapienate biosynthesis in MEFs with Tsc2 deletion, HUH7 hepatocellular carcinoma cells, and orthotopic HUH7 liver xenografts. In conclusion, we show that mTOR signaling and SREBP activity are sufficient to activate sapienate metabolism by increasing FADS2 expression. Consequently, targeting mTOR signaling can reduce sapienate metabolism in vivo.
MeSH term(s)	Animals ; Cell Line, Tumor ; Fatty Acid Desaturases/genetics ; Fatty Acid Desaturases/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Palmitic Acids/metabolism ; Prognosis ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction ; Sterol Regulatory Element Binding Protein 1/biosynthesis ; Sterol Regulatory Element Binding Protein 1/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Transcription, Genetic
Chemical Substances	Palmitic Acids ; RNA, Messenger ; Sterol Regulatory Element Binding Protein 1 ; delta(6)-hexadecenoic acid ; Fatty Acid Desaturases (EC 1.14.19.-) ; FADS2 protein, human (EC 1.14.19.3) ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
Language	English
Publishing date	2020-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.107806
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