bims-stacyt 2024-10-27 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–10–27
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

O-GlcNAcylation of enolase 1 serves as a dual regulator of aerobic glycolysis and immune evasion in colorectal cancer.
The signature of extracellular vesicles in hypoxic breast cancer and their therapeutic engineering.
Immunomodulatory Functions of TNF-Related Apoptosis-Inducing Ligand in Type 1 Diabetes.
Metabolic modulation of melanoma enhances the therapeutic potential of immune checkpoint inhibitors.
A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.
Glucose impacts onto the reciprocal reprogramming between mammary adipocytes and cancer cells.
A [18F]FDG PET based nomogram to predict cancer-associated cachexia and survival outcome: A multi-center study.
Targeting Mitochondrial Cholesterol Efflux via TCF21/ABCA10 Pathway to Enhance Cisplatin Efficacy in Ovarian Cancer.
P-stalk ribosomes act as master regulators of cytokine-mediated processes.
GDF15 knockout does not substantially impact perinatal body weight or neonatal outcomes in mice.

Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2408354121

O-GlcNAcylation of enolase 1 serves as a dual regulator of aerobic glycolysis and immune evasion in colorectal cancer.

Qiang Zhu, Jingchao Li, Haofan Sun, Zhiya Fan, Jiating Hu, Siyuan Chai, Bingyi Lin, Liming Wu, Weijie Qin, Yong Wang, Linda C Hsieh-Wilson, Wen Yi.

  Aerobic glycolysis and immune evasion are two key hallmarks of cancer. However, how these two features are mechanistically linked to promote tumor growth is not well understood. Here, we show that the glycolytic enzyme enolase-1 (ENO1) is dynamically modified with an O-linked β-N-acetylglucosamine (O-GlcNAcylation), and simultaneously regulates aerobic glycolysis and immune evasion via differential glycosylation. Glycosylation of threonine 19 (T19) on ENO1 promotes its glycolytic activity via the formation of active dimers. On the other hand, glycosylation of serine 249 (S249) on ENO1 inhibits its interaction with PD-L1, decreases association of PD-L1 with the E3 ligase STUB1, resulting in stabilization of PD-L1. Consequently, blockade of T19 glycosylation on ENO1 inhibits glycolysis, and decreases cell proliferation and tumor growth. Blockade of S249 glycosylation on ENO1 reduces PD-L1 expression and enhances T cell-mediated immunity against tumor cells. Notably, elimination of glycosylation at both sites synergizes with PD-L1 monoclonal antibody therapy to promote antitumor immune response. Clinically, ENO1 glycosylation levels are up-regulated and show a positive correlation with PD-L1 levels in human colorectal cancers. Thus, our findings provide a mechanistic understanding of how O-GlcNAcylation bridges aerobic glycolysis and immune evasion to promote tumor growth, suggesting effective therapeutic opportunities.

Keywords:  O-GlcNAcylation; cancer; enolase; glycolysis; immune evasion

DOI:  https://doi.org/10.1073/pnas.2408354121
Cell Commun Signal. 2024 Oct 21. 22(1): 512

The signature of extracellular vesicles in hypoxic breast cancer and their therapeutic engineering.

Baiheng Zhu, Kehao Xiang, Tanghua Li, Xin Li, Fujun Shi.

  Breast cancer (BC) currently ranks second in the global cancer incidence rate. Hypoxia is a common phenomenon in BC. Under hypoxic conditions, cells in the tumor microenvironment (TME) secrete numerous extracellular vesicles (EVs) to achieve intercellular communication and alter the metabolism of primary and metastatic tumors that shape the TME. In addition, emerging studies have indicated that hypoxia can promote resistance to tumor treatment. Engineered EVs are expected to become carriers for cancer treatment due to their high biocompatibility, low immunogenicity, high drug delivery efficiency, and ease of modification. In this review, we summarize the mechanisms of EVs in the primary TME and distant metastasis of BC under hypoxic conditions. Additionally, we highlight the potential applications of engineered EVs in mitigating the malignant phenotypes of BC cells under hypoxia.

Keywords:  Breast cancer; Engineered EVs; Extracellular vesicles; Hypoxia; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-024-01870-w
Cells. 2024 Oct 10. pii: 1676. [Epub ahead of print]13(20):

Immunomodulatory Functions of TNF-Related Apoptosis-Inducing Ligand in Type 1 Diabetes.

Marton Fogarasi, Simona Dima.

  Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D.

Keywords:  T cells; TRAIL; apoptosis; autoimmunity; immunoregulation; type 1 diabetes

DOI:  https://doi.org/10.3390/cells13201676
Front Oncol. 2024 ;14 1428802

Metabolic modulation of melanoma enhances the therapeutic potential of immune checkpoint inhibitors.

Zafer Gurel, Michael S Luy, Qianyun Luo, Nicholas L Arp, Amy K Erbe, Aparna H Kesarwala, Jing Fan, Randall J Kimple.

   Introduction: Lactate is a pivotal molecule with diverse functions in the metabolic reprogramming of cancer cells. Beyond its role in metabolism, lactate exerts a modulatory effect within the tumor microenvironment; it is utilized by stromal cells and has been implicated in the suppression of the immune response against the tumor.
Methods: Using in vitro assays (including flow cytometry, live-cell imaging and metabolic analyses), the impact of lactate dehydrogenase inhibitors (LDHIs) on melanoma cells were assessed. The therapeutic potential of LDHIs with immune checkpoint inhibitors (ICIs) were tested in vivo in murine models of melanoma tumors.
Results: A potent anti-proliferative effect (via both cell cycle alterations and enhanced apoptosis) of LDHIs, Oxamate (Oxa) and methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2), was found upon treatment of melanoma cell lines. Using a combination of Oxa and NHI-2, a synergistic effect to inhibit proliferation, glycolysis, and ATP production was observed. Metabolic analysis revealed significant alteration in glycolysis and oxidative phosphorylation, while metabolite profiling emphasized consequential effects on lactate metabolism and induced energy depletion by LDHIs. Detection of increased RANTES and MCP-1, with Oxa and NHI-2 treatment, prompted the consideration of combining LDHIs with ICIs. In vivo studies using a murine B78 melanoma tumor model revealed a significant improvement in treatment efficacy when LDHIs were combined with ICIs.
Conclusions: These findings propose the potential of targeting lactate metabolism to enhance the efficacy of ICI treatments in patients with melanoma.

Keywords:  LDH; NHI-2; cancer metabolism; immune checkpoint inhibitors; lactate; melanoma; oxamate

DOI:  https://doi.org/10.3389/fonc.2024.1428802
Int J Biol Sci. 2024 ;20(13): 5109-5126

A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.

Xuan Zhao, Tong Ren, Sijin Li, Xu Wang, Rui Hou, Zhangchun Guan, Dan Liu, Junnian Zheng, Ming Shi.

  Tumor-associated macrophages (TAMs) undergo metabolic reprogramming, encompassing glucose, amino acid, fatty acid metabolism, tricarboxylic acid (TCA) cycle, purine metabolism, and autophagy, within the tumor microenvironment (TME). The metabolic interdependencies between TAMs and tumor cells critically influence macrophage recruitment, differentiation, M2 polarization, and secretion of epithelial-mesenchymal transition (EMT)-related factors, thereby activating intratumoral EMT pathways and enhancing tumor cell invasion and metastasis. Tumor cell metabolic alterations, including hypoxia, metabolite secretion, aerobic metabolism, and autophagy, affect the TME's metabolic landscape, driving macrophage recruitment, differentiation, M2 polarization, and metabolic reprogramming, ultimately facilitating EMT, invasion, and metastasis. Additionally, macrophages can induce tumor cell EMT by reprogramming their aerobic glycolysis. Recent experimental and clinical studies have focused on the metabolic interactions between macrophages and tumor cells to control metastasis and inhibit tumor progression. This review highlights the regulatory role of TAM-tumor cell metabolic codependencies in EMT, offering valuable insights for TAM-targeted therapies in highly metastatic tumors. Modulating the metabolic interplay between tumors and TAMs represents a promising therapeutic strategy for treating patients with metastatic cancers.

Keywords:  Epithelial-mesenchymal transition; Metabolism; Tumor cells; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.7150/ijbs.99680
Sci Rep. 2024 10 21. 14(1): 24674

Glucose impacts onto the reciprocal reprogramming between mammary adipocytes and cancer cells.

Maria Rosaria Ambrosio, Michiel Adriaens, Kasper Derks, Teresa Migliaccio, Valerio Costa, Domenico Liguoro, Simona Cataldi, Vittoria D'Esposito, Giovanni Maneli, Rita Bassolino, Simone Di Paola, Marinella Pirozzi, Fabrizio Schonauer, Francesco D'Andrea, Francesco Beguinot, Ilja Arts, Pietro Formisano.

  An established hallmark of cancer cells is metabolic reprogramming, largely consisting in the exacerbated glucose uptake. Adipocytes in the tumor microenvironment contribute toward breast cancer (BC) progression and are highly responsive to metabolic fluctuations. Metabolic conditions characterizing obesity and/or diabetes associate with increased BC incidence and mortality. To explore BC-adipocytes interaction and define the impact of glucose in such dialogue, Mammary Adipose-derived Mesenchymal Stem Cells (MAd-MSCs) were differentiated into adipocytes and co-cultured with ER+ BC cells while exposed to glucose concentration resembling hyperglycemia or normoglycemia in humans (25mM or 5.5mM). The transcriptome of both cell types in co-culture as in mono-culture was profiled by RNA-Seq to define the impact of adipocytes on BC cells and viceversa (i), the action of glucose on BC cells, adipocytes (ii) and their crosstalk (iii). Noteworthy, we provided evidence that co-culture with adipocytes in a glucose-rich environment determined a re-program of BC cell transcriptome driving lipid accumulation, a hallmark of BC aggressiveness, promoting stem-like properties and reducing Tamoxifen responsiveness. Moreover, our data point out to a transcriptional effect through which BC cells induce adipocytes de-lipidation, paralleled by pluripotency gain, as source of lipids when glucose lowering occurs. Thus, modulating plasticity of peri-tumoral adipocytes may represent a key point for halting BC progression in metabolically unbalanced patients.

Keywords:  Adipogenesis; Breast Cancer; Glucose; Mammary Adipocytes; Transcriptional signatures; Tumor Microenvironment

DOI:  https://doi.org/10.1038/s41598-024-76522-7
Nutrition. 2024 Oct 01. pii: S0899-9007(24)00242-9. [Epub ahead of print]129 112593

A [18F]FDG PET based nomogram to predict cancer-associated cachexia and survival outcome: A multi-center study.

Yang Jiang, Mouqing Huang, Yufei Zhao, Jingyue Dai, Qingwen Yang, Xingzhe Tang, Xinxiang Li, Ying Cui, Jingqi Zhang, Jialu Sun, Lin Fu, Hui Mao, Xin-Gui Peng.

   OBJECTIVES: Cancer patients with cachexia face poor prognosis and shortened survival. Early diagnosis and accurate prognosis prediction remain challenging. This multi-center study aims to develop and externally validate a nomogram integrating [18F]fluoro-2-deoxy-D-glucose ([18F]FDG) PET findings and routine clinical biochemistry tests for predicting cancer-associated cachexia, while also assessing its potential prognostic value.
RESEARCH METHODS & PROCEDURES: A retrospective analysis of 658 cancer patients (390 in the development cohort, 268 in the validation cohort) utilized [18F]FDG PET/CT data from two centers. Logistic regression identified organ-specific standardized uptake values (SUVs) and clinical variables associated with cancer-associated cachexia. Diagnostic accuracy, discriminative ability, and clinical effectiveness were assessed using area under the curve (AUC), calibration curve, and decision curve. Nomogram predictability for overall survival was evaluated through Cox regression and Kaplan-Meier curves.
RESULTS: The combined nomogram incorporating age (odds ratio [OR] = 1.893; P = 0.012), hemoglobin (OR = 2.591; P < 0.001), maximum SUV of the liver (OR = 3.646; P < 0.001), and minimum SUV of the subcutaneous fat (OR = 5.060; P < 0.001) achieved good performance in predicting cancer-associated cachexia (AUC = 0.807/0.726, development/validation). Calibration and decision curve analyses confirmed its clinical effectiveness. Kaplan-Meier curves analysis showed that overall survival can be categorized using the combined nomogram (P < 0.001).
CONCLUSION: Combining radiological information from clinical standard [18F]FDG PET data from cancer patients with biochemical results in their routine clinical blood tests through a well-constructed nomogram enables predicting cachexia and its effect on the prognosis of cancer patients.

Keywords:  Adipose tissue; Cachexia; Cancer; Liver; Positron emission tomography; [(18)F]fluoro-2-deoxy-D-glucose

DOI:  https://doi.org/10.1016/j.nut.2024.112593
Biochem Genet. 2024 Oct 22.

Targeting Mitochondrial Cholesterol Efflux via TCF21/ABCA10 Pathway to Enhance Cisplatin Efficacy in Ovarian Cancer.

Li Li, Hui Cheng, Yang Peng, Dihong Tang.

  Cisplatin (DDP) resistance is one of the causes of treatment failure for ovarian cancer (OV). Mitochondrial cholesterol level was reported to be associated with OV chemoresistance. We found that ABCA10, a potential cholesterol transport protein, was highly expressed in ovarian tissues and downregulated in OV tissues. Our study aimed to explore TCF21/ABCA10 axis resistance to DDP therapy in ovarian cancer based on regulating mitochondrial cholesterol efflux. Thirty epithelial ovarian cancer tumors and thirty ovarian tissues from non-cancer patients were collected. Western blot and RT-qPCR were used to measure ABCA10 and TCF21 expression levels in these tissues, as well as in a human ovarian epithelial cell line (IOSE-80), OV cells (A2780 and SKOV3), and DDP-resistant OV cell lines (A2780/DDP and SKOV3/DDP). IOSE-80 cells were also infected with ABCA10 knockdown lentivirus to identify the most effective ABCA10 knockdown plasmid. Lentiviral infection was used to create ABCA10 knockdown, ABCA10 overexpression, and TCF21 overexpression anti-DDP OV cell lines. Cell proliferation was detected by CCK-8 and EDU staining, flow cytometry for apoptosis, MTT for metabolic activity, calcium-induced Cytochrome C release, and mitochondrial matrix swelling for mitochondrial function and Oil Red O staining for lipid accumulation. Cholesterol metabolism was evaluated by measuring mitochondrial cholesterol and cholesterol efflux. Protein concentration was determined using the BCA method. A dual-luciferase reporter assay confirmed TCF21's interaction with ABCA10. ChIP also verified this interaction. The mRNA level (P < 0.01) and protein level (P < 0.001) of ABCA10 were downregulated in cancer tissues of OV patients relative to normal ovarian tissues. Relative to human ovarian epithelial cells, ABCA10 expression was significantly downregulated in OV cells (P < 0.01) and even more significantly downregulated in DDP-resistant OV cells (P < 0.001). Compared to the group treated solely with DDP, the overexpression of ABCA10 significantly inhibited the proliferation of DDP-resistant OV cells (P < 0.01), markedly reduced the staining intensity of EDU in these cells (P < 0.05), and substantially accelerated apoptosis in DDP-resistant OV cells (P < 0.01).Overexpression of ABCA10 further accelerated Cytochrome C expression and mitochondrial matrix swelling in DDP-resistant OV cells compared to the DDP-alone group (P < 0.01). The addition of cholesterol reversed the decrease in lipid accumulation, the decrease in mitochondrial cholesterol levels (P < 0.05), and the increase in cholesterol efflux (P < 0.01) in DDP-resistant OV cells caused by overexpression of ABCA10. The transcription factor TCF21 was bound to the promoter of ABCA10. Overexpression of TCF21 significantly increased ABCA10 expression in DDP-resistant OV cells (P < 0.01) and increased cytochrome C expression in A2780/DDP (P < 0.05) and SKOV3/DDP (P < 0.01) cells, with accelerated mitochondrial matrix swelling in A2780/DDP (P < 0.01) and SKOV3/DDP (P < 0.001) cells, while knockdown of ABCA10 reversed these effects. Our study found that TCF21 boosts ABCA10 expression, which in turn reduces DDP resistance in OV cells by enhancing mitochondrial cholesterol efflux. This mechanism increases the sensitivity of DDP-resistant OV cells to DDP. Our findings will provide new therapeutic targets for the treatment of ovarian cancer.

Keywords:  ABCA10; Cisplatin resistance; Lipid metabolism reprogramming; Mitochondrial cholesterol efflux; Ovarian cancer; TCF21

DOI:  https://doi.org/10.1007/s10528-024-10939-7
Cell. 2024 Oct 14. pii: S0092-8674(24)01139-5. [Epub ahead of print]

P-stalk ribosomes act as master regulators of cytokine-mediated processes.

Anna Dopler, Ferhat Alkan, Yuval Malka, Rob van der Kammen, Kelly Hoefakker, Daniel Taranto, Naz Kocabay, Iris Mimpen, Christel Ramirez, Elke Malzer, Olga I Isaeva, Mandy Kerkhoff, Anastasia Gangaev, Joana Silva, Sofia Ramalho, Liesbeth Hoekman, Maarten Altelaar, Roderick Beijersbergen, Leila Akkari, Jonathan Wilson Yewdell, Pia Kvistborg, William James Faller.

  Inflammatory cytokines are pivotal to immune responses. Upon cytokine exposure, cells enter an "alert state" that enhances their visibility to the immune system. Here, we identified an alert-state subpopulation of ribosomes defined by the presence of the P-stalk. We show that P-stalk ribosomes (PSRs) are formed in response to cytokines linked to tumor immunity, and this is at least partially mediated by P-stalk phosphorylation. PSRs are involved in the preferential translation of mRNAs vital for the cytokine response via the more efficient translation of transmembrane domains of receptor molecules involved in cytokine-mediated processes. Importantly, loss of the PSR inhibits CD8+ T cell recognition and killing, and inhibitory cytokines like transforming growth factor β (TGF-β) hinder PSR formation, suggesting that the PSR is a central regulatory hub upon which multiple signals converge. Thus, the PSR is an essential mediator of the cellular rewiring that occurs following cytokine exposure via the translational regulation of this process.

Keywords:  P-stalk; T cells; cytokines; melanoma; ribosome

DOI:  https://doi.org/10.1016/j.cell.2024.09.039
Endocrinology. 2024 Oct 24. pii: bqae143. [Epub ahead of print]

GDF15 knockout does not substantially impact perinatal body weight or neonatal outcomes in mice.

Molly C Mulcahy, Noura El Habbal, JeAnna R Redd, Haijing Sun, Brigid E Gregg, Dave Bridges.

  Growth differentiation factor-15 (GDF15) increases in circulation during pregnancy and has been implicated in food intake, weight loss, complications of pregnancy, and metabolic illness. We used a Gdf15 knockout mouse model (Gdf15-/-) to assess the role of GDF15 in body weight regulation and food intake during pregnancy. We found that Gdf15-/- dams consumed a similar amount of food and gained comparable weight during the course of pregnancy compared to Gdf15+/+ dams. Insulin sensitivity on gestational day 16.5 was also similar between genotypes. In the postnatal period, litter size, and survival rates were similar between genotypes. There was a modest reduction in birth weight of Gdf15-/- pups, but this difference was no longer evident postnatal day 3.5 to 14.5. We observed no detectable differences in milk volume production or milk fat percentage. These data suggest that GDF15 is dispensable for changes in food intake, and body weight as well as insulin sensitivity during pregnancy in a mouse model.

Keywords:  GDF15; glucocorticoids; pregnancy; weight gain

DOI:  https://doi.org/10.1210/endocr/bqae143