bims-stacyt 2024-01-21 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–01–21
eleven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.
Angiogenesis is promoted by hypoxic cervical carcinoma-derived extracellular vesicles depending on the endothelial cell environment.
Acute Exercise Increases GDF15 and Unfolded Protein Response/Integrated Stress Response in Muscle in Type 2 diabetes.
Suppression of malignant melanoma by knocking down growth differentiation factor-15 via inhibiting PTEN/PI3K/AKT signaling pathway.
Lipopolysaccharide-mediated ATP signaling regulates interleukin-6 mRNA expression via the P2-purinoceptor in human dental pulp cells.
D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells.
Tolerable glycometabolic stress boosts cancer cell resilience through altered N-glycosylation and Notch signaling activation.
Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer.
Elevated 18F-FDG uptake in subcutaneous adipose tissue correlates negatively with nutritional status and prognostic survival in cachexia patients with gastric cancer.
The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.
Nutrient sensing in macrophages linked to reorganized tumor vasculature.

Sci Rep. 2024 01 18. 14(1): 1563

ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.

Sarah H Bjorkman, Alex Marti, Jayashree Jena, Luis Miguel García-Peña, Eric T Weatherford, Kevin Kato, Jivan Koneru, Jason Chen, Ayushi Sood, Matthew J Potthoff, Christopher M Adams, E Dale Abel, Renata O Pereira.

In brown adipose tissue (BAT), short-term cold exposure induces the activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). Induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, partially by increasing FGF21 expression. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis under physiological stress by generating mice selectively lacking either Atf4 (ATF4 BKO) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum-fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue. Conversely, despite having reduced browning, FGF21 BKO mice had preserved core body temperature after cold exposure. Mechanistically, ATF4, but not FGF21, regulates amino acid import and metabolism in response to cold, likely contributing to BAT thermogenic capacity under ad libitum-fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis under fed conditions likely in a FGF21-independent manner, in part via increased amino acid uptake and metabolism.

DOI: https://doi.org/10.1038/s41598-024-52004-8
Vascul Pharmacol. 2024 Jan 17. pii: S1537-1891(24)00001-6. [Epub ahead of print] 107276

Angiogenesis is promoted by hypoxic cervical carcinoma-derived extracellular vesicles depending on the endothelial cell environment.

E Orozco-García, V Getova, J C Calderón, M C Harmsen, R Narvaez-Sanchez.

   INTRODUCTION: Cancer needs perfusion for its growth and metastasis. Cancer cell-derived extracellular vesicles (CA-EVs) alter the tumor microenvironment (TME), potentially promoting angiogenesis. We hypothesize that conditions in the tumor, e.g., hypoxia, and in the target cells of the TME, e.g., nutrient deprivation or extracellular matrix, can affect the angiogenic potential of CA-EVs, which would contribute to explaining the regulation of tumor vascularization and its influence on cancer growth and metastasis.
METHODS: CA-EVs were isolated and characterized from cervical carcinoma cell lines HeLa and SiHa cultured under normoxia and hypoxia, and their angiogenic potential was evaluated in vitro in three endothelial cells (ECs) lines and aortic rings, cultured in basal (growth factor-reduced) or complete medium.
RESULTS: Hypoxia increased EV production 10-100 times and protein content 2-4 times compared to normoxic CA-EVs. HeLa-EVs contained six times more RNA than SiHa-EVs, and this concentration was not affected by hypoxia. Treatment with CA-EVs increased tube formation and sprouting in ECs and aortic rings cultured in basal medium and long-term stabilized the stablished vascular networks formed by ECs cultured in complete medium.
CONCLUSION: Hypoxia differentially affects CA-EVs in a cell line-dependent manner. The cellular environment (nutrient availability and extracellular matrix scaffold) influences the effect of CA-EV on the angiogenic potential of ECs.

Keywords:  Angiogenesis; Cell communication; Extracellular matrix; Extracellular vesicles; Vascular remodeling

DOI:  https://doi.org/10.1016/j.vph.2024.107276
J Clin Endocrinol Metab. 2024 Jan 18. pii: dgae032. [Epub ahead of print]

Acute Exercise Increases GDF15 and Unfolded Protein Response/Integrated Stress Response in Muscle in Type 2 diabetes.

Rugivan Sabaratnam, Jonas M Kristensen, Andreas J T Pedersen, Rikke Kruse, Aase Handberg, Jørgen F P Wojtaszewski, Kurt Højlund.

   CONTEXT: Regular exercise is a key prevention strategy for obesity and type 2 diabetes (T2D). Exerkines secreted in response to exercise or recovery may contribute to improved systemic metabolism. Conversely, an impaired exerkine response to exercise and recovery may contribute to cardiometabolic diseases.
OBJECTIVE: We investigated if the exercise-induced regulation of the exerkine, growth/differentiation factor 15 (GDF15) and its putative upstream regulators of the unfolded protein response (UPR)/integrated stress response (ISR) is impaired in skeletal muscle in patients with T2D compared with weight-matched glucose-tolerant men.
METHODS: Thirteen male patients with T2D and 14 age- and weight-matched overweight/obese glucose-tolerant men exercised at 70% of VO2max for 1-h. Blood and skeletal muscle biopsies were sampled before, immediately after, and 3-h into recovery. Serum and muscle transcript levels of GDF15 and key markers of UPR/ISR were determined. Additionally, protein/phosphorylation levels of key regulators in UPR/ISR were investigated.
RESULTS: Acute exercise increased muscle gene expression and serum GDF15 levels in both groups. In recovery, muscle expression of GDF15 decreased toward baseline, whereas serum GDF15 remained elevated. In both groups, acute exercise increased the expression of UPR/ISR markers, including ATF4, CHOP, EIF2K3 (encoding PERK) and PPP1R15A (encoding GADD34), of which only CHOP remained elevated 3-h into recovery. Downstream molecules of the UPR/ISR including XBP1-U, XBP1-S, and EDEM1 were increased with exercise and 3-h into recovery in both groups. The phosphorylation levels of eIF2α-Ser51, a common marker of UPR and ISR, increased immediately after exercise in controls, but decreased 3-h into recovery in both groups.
CONCLUSION: In conclusion, exercise-induced regulation of GDF15 and key markers of UPR/ISR are not compromised in patients with type 2 diabetes compared with weight-matched controls.

Keywords:  GDF15; Type 2 diabetes; UPR/ISR; exerkine; obesity; skeletal muscle

DOI:  https://doi.org/10.1210/clinem/dgae032
J Cancer. 2024 ;15(4): 1115-1123

Suppression of malignant melanoma by knocking down growth differentiation factor-15 via inhibiting PTEN/PI3K/AKT signaling pathway.

Jun Zhou, Caifeng Chen.

  Background: Melanoma is a highly malignant tumor, and it is characterized by high mortality. Growth differentiation factor 15 (GDF15) and PTEN/PI3K/AKT signaling pathway have been proved to be related with regulation of tumors. If GDF15 could regulate melanoma through targeting PTEN/PI3K/AKT signaling pathway remain unclear. Methods: EdU staining, wound healing, Transwell assay, and flow cytometry were performed to measure cell proliferation, migration, invasion, and apoptosis. GEPIA and TCGA data bases were applied to analyze the relationship between GDF15 and prognosis. Results: We found that high expression of GDF15 suggested lower survival of melanoma patients, and is positively linked with advanced stage through analysis with GEPIA and TCGA data bases. Knockdown of GDF15 greatly inhibited the migration, invasion and proliferation ability of both M14 and M21 cells, but promoted cell apoptosis. However, the influence of GDF15 on M14 and M21 cells were reversed by 740Y-P, the activator of PTEN/PI3K/AKT signaling pathway. In addition, 740Y-P significantly reversed the influence of sh-GDF15 on the epithelial-mesenchymal transition (EMT) related proteins expression in M14 and M21 cell lines. Significant higher expression of GDF15 in melanoma was observed. In addition, the inhibition of PTEN/PI3K/AKT signaling pathway by knocking down GDF15 was observed in both M14 and M21 cell lines. sh-GDF15 greatly decreased the resistance of M14 and M21 to chemotherapy drugs, docetaxel and doxorubicin. Conclusions: GDF15 regulated the cell proliferation, apoptosis, migration, invasion, and EMT process of M14 and M21 cell lines through targeting PTEN/PI3K/AKT signaling pathway. This research provides a novel prevention and treatment strategy for melanoma.

Keywords:  740Y-P; AKT; GDF15; PI3K; PTEN; malignant melanoma

DOI:  https://doi.org/10.7150/jca.91892
Cell Biol Int. 2024 Jan 15.

Lipopolysaccharide-mediated ATP signaling regulates interleukin-6 mRNA expression via the P2-purinoceptor in human dental pulp cells.

Ai Orimoto, Chiaki Kitamura, Kentaro Ono.

  Dental pulp cells play a crucial role in maintaining the balance of the pulp tissue. They actively respond to bacterial inflammation by producing proinflammatory cytokines, particularly interleukin-6 (IL-6). While many cell types release adenosine triphosphate (ATP) in response to various stimuli, the mechanisms and significance of ATP release in dental pulp cells under inflammatory conditions are not well understood. This study aimed to investigate ATP release and its relationship with IL-6 during the inflammatory response in immortalized human dental pulp stem cells (hDPSC-K4DT) following lipopolysaccharide (LPS) stimulation. We found that hDPSC-K4DT cells released ATP extracellularly when exposed to LPS concentrations above 10 μg/mL. ATP release was exclusively attenuated by N-ethylmaleimide, whereas other inhibitors, including clodronic acid (a vesicular nucleotide transporter inhibitor), probenecid (a selective pannexin-1 channel inhibitor), meclofenamic acid (a selective connexin 43 inhibitor), suramin (a nonspecific P2 receptor inhibitor), and KN-62 (a specific P2X7 antagonist), did not exhibit any effect. Additionally, LPS increased IL-6 mRNA expression, which was mitigated by the ATPase apyrase enzyme, N-ethylmaleimide, and suramin, but not by KN-62. Moreover, exogenous ATP induced IL-6 mRNA expression, whereas ATPase apyrase, N-ethylmaleimide, and suramin, but not KN-62, diminished ATP-induced IL-6 mRNA expression. Overall, our findings suggest that LPS-induced ATP release stimulates the IL-6 pathway through P2-purinoceptor, indicating that ATP may function as an anti-inflammatory signal, contributing to the maintenance of dental pulp homeostasis.

Keywords:  adenosine triphosphate release; auto-regulation; immortalized human dental pulp stem cells; interleukin-6; lipopolysaccharide

DOI:  https://doi.org/10.1002/cbin.12120
Haematologica. 2024 Jan 18.

D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells.

Kathrin Hammon, Kathrin Renner, Michael Althammer, Florian Voll, Nathalie Babl, Sonja-Maria Decking, Peter J Siska, Carina Matos, Zugey Elizabeth Cárdenas Conejo, Karina Mendes, Friederike Einwag, Heiko Siegmund, Sabine Iberl, Raffaela S Berger, Katja Dettmer, Rebecca Schoenmehl, Christoph Brochhausen, Wolfgang Herr, Peter J Oefner, Michael Rehli, Simone Thomas, Marina Kreutz.

D-2-hydroxyglutarate (D-2-HG) accumulates in primary acute myeloid leukemia (AML) patients with mutated isocitrate dehydrogenase (IDH) and other malignancies. D-2-HG suppresses antitumor T cell immunity but little is known about potential effects on non-malignant myeloid cells. Here we show that D-2-HG impairs human but not murine dendritic cell (DC) differentiation, resulting in a tolerogenic phenotype with low major histocompatibility (MHC) class II expression. In line, IDH-mutated AML blasts exhibited lower expression of HLA-DP and were less susceptible to lysis by HLA-DP-specific T cells. Interestingly, D-2-HG reprogrammed metabolism towards increased lactate production in DCs and AML besides its expected impact on DNA demethylation. Vitamin C accelerated DNA demethylation, but only the combination of vitamin C and glycolytic inhibition lowered lactate levels and supported MHC class II expression. Our results indicate an unexpected link between the immunosuppressive metabolites 2-HG and lactic acid and suggest a potentially novel therapeutic strategy with combinations of anti-glycolytic drugs and epigenetic modulators (hypomethylating agents) or other therapeutics for the treatment of AML.

DOI: https://doi.org/10.3324/haematol.2023.283597
Cell Death Dis. 2024 Jan 15. 15(1): 53

Tolerable glycometabolic stress boosts cancer cell resilience through altered N-glycosylation and Notch signaling activation.

Shungo Iwamoto, Takashi Kobayashi, Hisatoshi Hanamatsu, Ikuko Yokota, Yukiko Teranishi, Akiho Iwamoto, Miyu Kitagawa, Sawako Ashida, Ayane Sakurai, Suguru Matsuo, Yuma Myokan, Aiyu Sugimoto, Ryo Ushioda, Kazuhiro Nagata, Noriko Gotoh, Kazuki Nakajima, Takashi Nishikaze, Jun-Ichi Furukawa, Naoki Itano.

Chronic metabolic stress paradoxically elicits pro-tumorigenic signals that facilitate cancer stem cell (CSC) development. Therefore, elucidating the metabolic sensing and signaling mechanisms governing cancer cell stemness can provide insights into ameliorating cancer relapse and therapeutic resistance. Here, we provide convincing evidence that chronic metabolic stress triggered by hyaluronan production augments CSC-like traits and chemoresistance by partially impairing nucleotide sugar metabolism, dolichol lipid-linked oligosaccharide (LLO) biosynthesis and N-glycan assembly. Notably, preconditioning with either low-dose tunicamycin or 2-deoxy-D-glucose, which partially interferes with LLO biosynthesis, reproduced the promoting effects of hyaluronan production on CSCs. Multi-omics revealed characteristic changes in N-glycan profiles and Notch signaling activation in cancer cells exposed to mild glycometabolic stress. Restoration of N-glycan assembly with glucosamine and mannose supplementation and Notch signaling blockade attenuated CSC-like properties and further enhanced the therapeutic efficacy of cisplatin. Therefore, our findings uncover a novel mechanism by which tolerable glycometabolic stress boosts cancer cell resilience through altered N-glycosylation and Notch signaling activation.

DOI: https://doi.org/10.1038/s41419-024-06432-z
J Clin Invest. 2024 Jan 16. pii: e175445. [Epub ahead of print]134(2):

Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer.

Corey Dussold, Kaylee Zilinger, Jillyn Turunen, Amy B Heimberger, Jason Miska.

Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal role in tumor biology, yet their metabolic influence on tumor growth and antitumor immune responses remains inadequately understood. This Review explores the metabolic landscape of tumor-associated macrophages, including the immunoregulatory roles of glucose, fatty acids, glutamine, and arginine, alongside the tools used to perturb their metabolism to promote antitumor immunity. The confounding role of metabolic inhibitors on our interpretation of myeloid metabolic phenotypes will also be discussed. A binary metabolic schema is currently used to describe macrophage immunological phenotypes, characterizing inflammatory M1 phenotypes, as supported by glycolysis, and immunosuppressive M2 phenotypes, as supported by oxidative phosphorylation. However, this classification likely underestimates the variety of states in vivo. Understanding these nuances will be critical when developing interventional metabolic strategies. Future research should focus on refining drug specificity and targeted delivery methods to maximize therapeutic efficacy.

DOI: https://doi.org/10.1172/JCI175445
Clin Nutr. 2024 Jan 09. pii: S0261-5614(24)00006-2. [Epub ahead of print]43(2): 567-574

Elevated 18F-FDG uptake in subcutaneous adipose tissue correlates negatively with nutritional status and prognostic survival in cachexia patients with gastric cancer.

Diya Sun, Hongyan Yin, Xiao Liu, Zuoyou Ding, Lei Shen, Szechun Sah, Jun Han, Guohao Wu.

   BACKGROUND: Browning of white adipose tissue is a crucial factor contributing to adipose loss in cachexia patients, detectable via 18F-Fluorodeoxyglucose (18F-FDG) uptake. The present study elucidates the clinical relevance of 18F-FDG uptake in the subcutaneous adipose tissue of gastric cancer patients, specifically focusing on adipose browning and its implications on patient clinical parameters and prognosis.
METHODS: This investigation encompassed 770 gastric cancer patients, with PET-CT imaging and clinical data meticulously combined. The 18F-FDG uptake in subcutaneous adipose tissue at the third lumbar layer was quantified, and its correlation with clinical parameters, particularly those related to nutritional status and fat metabolism, was examined. Kaplan-Meier curves were subsequently employed to probe the relationship between 18F-FDG uptake and overall survival.
RESULTS: Of the 770 gastric cancer patients, 252 exhibited cancer-associated cachexia, while 518 did not. Cachectic patients demonstrated elevated 18F-FDG uptake in subcutaneous adipose tissue relative to non-cachectic patients (P < 0.001). Increased 18F-FDG uptake was also correlated with reduced plasma concentrations of albumin, prealbumin, hemoglobin, platelets, cholesterol, apolipoprotein A, low-density lipoprotein, and elevated IL-6 concentrations (all P < 0.05). A significant inverse correlation was observed between 18F-FDG uptake and BMI, albumin, low-density lipoprotein, cholesterol, and apolipoprotein A (all P < 0.05). Patients with higher 18F-FDG uptake exhibited diminished overall survival rates compared to those with lower 18F-FDG uptake (P = 0.0065). Furthermore, 18F-FDG uptake in subcutaneous adipose tissue was an independent prognostic indicator in gastric cancer patients (P = 0.028).
CONCLUSIONS: Browning of subcutaneous adipose tissue was markedly elevated in cachectic gastric cancer patients compared to non-cachectic counterparts. Increased 18F-FDG uptake in subcutaneous adipose tissue in cachectic gastric cancer patients was inversely correlated with nutritional status and survival prognosis.

Keywords:  18F-FDG uptake; Adipose browning; Cancer-associated cachexia; Gastric cancer; Subcutaneous adipose tissue

DOI:  https://doi.org/10.1016/j.clnu.2024.01.006
PLoS Biol. 2024 Jan;22(1): e3002406

The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.

Mona Nazemi, Bian Yanes, Montserrat Llanses Martinez, Heather J Walker, Khoa Pham, Mark O Collins, Frederic Bard, Elena Rainero.

Breast tumours are embedded in a collagen I-rich extracellular matrix (ECM) network, where nutrients are scarce due to limited blood flow and elevated tumour growth. Metabolic adaptation is required for cancer cells to endure these conditions. Here, we demonstrated that the presence of ECM supported the growth of invasive breast cancer cells, but not non-transformed mammary epithelial cells, under amino acid starvation, through a mechanism that required macropinocytosis-dependent ECM uptake. Importantly, we showed that this behaviour was acquired during carcinoma progression. ECM internalisation, followed by lysosomal degradation, contributed to the up-regulation of the intracellular levels of several amino acids, most notably tyrosine and phenylalanine. This resulted in elevated tyrosine catabolism on ECM under starvation, leading to increased fumarate levels, potentially feeding into the tricarboxylic acid (TCA) cycle. Interestingly, this pathway was required for ECM-dependent cell growth and invasive cell migration under amino acid starvation, as the knockdown of p-hydroxyphenylpyruvate hydroxylase-like protein (HPDL), the third enzyme of the pathway, opposed cell growth and motility on ECM in both 2D and 3D systems, without affecting cell proliferation on plastic. Finally, high HPDL expression correlated with poor prognosis in breast cancer patients. Collectively, our results highlight that the ECM in the tumour microenvironment (TME) represents an alternative source of nutrients to support cancer cell growth by regulating phenylalanine and tyrosine metabolism.

DOI: https://doi.org/10.1371/journal.pbio.3002406
Cancer Res. 2024 Jan 19.

Nutrient sensing in macrophages linked to reorganized tumor vasculature.

Hilda L Chan, Xiang H-F Zhang.

Macrophages are plastic immune cells that have varying functions dependent on stimulation from their environment. In a recent issue of Immunity, Do and colleagues demonstrated that activating mechanistic target of rapamycin complex 1 signaling in tumor macrophages alters their metabolism, localization, and function. Specifically, these tumor macrophages promote vascular remodeling that develops a hypoxic environment toxic to cancer cells. This culminates in a tangible reduction in tumor burden in a murine model of breast cancer. Their findings reveal a unique strategy to promote vascular remodeling through macrophage polarization and thereby highlight the intimate connections between macrophage metabolism and function. Additionally, their model highlights parallels between tumor progression and wound healing contexts while emphasizing the amplified effect of small perturbations to a tumor ecosystem.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0201