bims-stacyt 2024-11-17 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–11–17
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Daily GDF15 treatment has sex-specific effects on body weight and food intake and does not enhance the effects of voluntary physical activity in mice.
Metformin inhibits migration and epithelial-to-mesenchymal transition in non-small cell lung cancer cells through AMPK-mediated GDF15 induction.
Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation.
Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment.
Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling.
Leukemia Inhibitory Factor Receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr-/- mice.
ACVR2B polymorphism, Adiponectin, and GDF-15 levels as biomarkers for cachexia in gastrointestinal cancer.
Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer.
Change in interleukin (IL)-6, 8, and 10 and its association with an increase in core temperature following a 7-mile running race in the warm weather.
A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.

J Physiol. 2024 Nov 09.

Daily GDF15 treatment has sex-specific effects on body weight and food intake and does not enhance the effects of voluntary physical activity in mice.

Stewart Jeromson, Michael Akcan, Bradley Baranowski, Meagan Arbeau, Annalaura Bellucci, David C Wright.

  Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that suppresses food intake and causes weight loss. GDF15 also reduces voluntary physical activity and, thus, it is not clear whether combining GDF15 with exercise will be beneficial or if reductions in food intake would be offset by decreases in physical activity. We investigated how GDF15 treatment combined with voluntary wheel running (VWR) would impact weight gain, food intake, adiposity and indices of metabolic health in mice. High-fat fed male and female mice underwent daily GDF15 treatments and were given access to voluntary running wheels, or not, for 11 days. In both sexes, VWR prevented weight gain. In males, GDF15 reduced food intake, as well as attenuated weight gain and the accumulation of adipose tissue, with no additional effect of VWR. In female mice, GDF15 did not impact body weight gain or body composition. GDF15 acutely reduced food intake in female mice but this was followed by a period of rebound hyperphagia and consequently GDF15 did not reduce total food intake in female mice. GDF15 treatment reduced wheel running distance in both sexes. There were main effects of VWR to improve glucose tolerance in female but not male mice. These findings show that GDF15 has sex-specific effects on food intake and consequently weight gain and adiposity. There is no added benefit of combining GDF15 and voluntary physical activity for weight loss. Adaptive responses to acute caloric restriction induced by GDF15 might limit its effectiveness as a weight loss tool in females. KEY POINTS: GDF15 is a stress-induced signalling factor that reduces food intake and voluntary physical activity. It is not known whether combining GDF15 treatment with voluntary wheel running would impart beneficial combined effects in attenuating weight gain and the accumulation of adipose tissue. In the present study, we demonstrate that GDF15 reduces food intake and prevents weight gain in male but not female mice consuming a high-fat diet and also that combining GDF15 with voluntary wheel running (VWR) does not lead to a greater dampening of weight gain. In female mice, GDF15 acutely reduced food intake, but this was followed by a period of rebound hyperphagia resulting in no differences in total food intake. In both sexes, VWR was equivalent, or superior to GDF15 in preventing weight gain.

Keywords:  GDF15; food intake; mice; obesity; physical activity

DOI:  https://doi.org/10.1113/JP287256
Eur J Pharmacol. 2024 Nov 09. pii: S0014-2999(24)00817-3. [Epub ahead of print] 177127

Metformin inhibits migration and epithelial-to-mesenchymal transition in non-small cell lung cancer cells through AMPK-mediated GDF15 induction.

Hongyu Zhou, Jun Xiao, Qi Cheng, Wen Wang, He Peng, Xiaojian Lin, Jiajun Chen, Xingya Wang.

The growth differentiation factor 15 (GDF15) may serve as a biomarker of metformin, which mediates the bodyweight lowering effect of metformin. However, whether GDF15 also serves as a molecular target of metformin to inhibit carcinogenesis remains largely unknown. This study examined the role and molecular mechanisms of GDF15 in the anticancer effects of metformin in non-small cell lung cancer (NSCLC) cells, which has never been reported before. We found that metformin significantly inhibited the migration of NSCLC A549 and NCI-H460 cells and reduced the expression of epithelial-to-mesenchymal transition (EMT)-related molecules, including neuro-cadherin (N-cadherin), matrix metalloproteinase 2 (MMP2), and the zinc finger transcription factor Snail, but increased epithelial cadherin (E-cadherin) expression. Furthermore, metformin increased GDF15 and its upstream transcription factors activated transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP) expressions and increased AMP-activated protein kinase (AMPK) phosphorylation in NSCLC cells. GDF15 siRNA partially reverses the inhibitory effect of metformin on NSCLC cell migration. Moreover, metformin-induced increases in GDF15, CHOP, and ATF4 expression and the inhibition of migration were partially reversed by treatment with Compound C, a specific AMPK inhibitor. Meanwhile, metformin significantly inhibited NCI-H460 xenograft tumor growth in nude mice, increased GDF15 expression, and regulated EMT- and migration-related protein expression in xenograft tumors. In conclusion, our results provide novel insights into revealing that GDF15 can serve as a potential molecular target of metformin owing to its anti-cancer effect in NSCLC, which is mediated by AMPK activation.

DOI: https://doi.org/10.1016/j.ejphar.2024.177127
J Clin Invest. 2024 Nov 15. pii: e176851. [Epub ahead of print]134(22):

Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation.

Shuai Wang, Tengfei Huang, Qiulian Wu, Huairui Yuan, Xujia Wu, Fanen Yuan, Tingting Duan, Suchet Taori, Yingming Zhao, Nathaniel W Snyder, Dimitris G Placantonakis, Jeremy N Rich.

  Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.

Keywords:  Adult stem cells; Brain cancer; Epigenetics; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI176851
Cell Rep. 2024 Nov 12. pii: S2211-1247(24)01323-8. [Epub ahead of print]43(11): 114972

Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment.

Xu Han, Michelle Burrows, Laura C Kim, Jimmy P Xu, Will Vostrejs, Tran Ngoc Van Le, Carson Poltorack, Yanqing Jiang, Edna Cukierman, Ben Z Stanger, Kim A Reiss, Sydney M Shaffer, Clementina Mesaros, Brian Keith, M Celeste Simon.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with abundant cancer-associated fibroblasts (CAFs) creating hallmark desmoplasia that limits oxygen and nutrient delivery. This study explores the importance of lipid homeostasis under stress. Exogenous unsaturated lipids, rather than de novo synthesis, sustain PDAC cell viability by relieving endoplasmic reticulum (ER) stress under nutrient scarcity. Furthermore, CAFs are less hypoxic than adjacent malignant cells in vivo, nominating them as a potential source of unsaturated lipids. CAF-conditioned medium promotes PDAC cell survival upon nutrient and oxygen deprivation, an effect reversed by delipidation. Lysophosphatidylcholines (LPCs) are particularly enriched in CAF-conditioned medium and preferentially taken up by PDAC cells, where they are converted to phosphatidylcholine (PC) to sustain membrane integrity. Blocking LPC-to-PC conversion inhibits PDAC cell survival and increases ER stress. These findings show a critical lipid "cross-feeding" mechanism that promotes PDAC cell survival, offering a potential metabolic target for treatment.

Keywords:  CP: Cancer; CP: Metabolism; fibroblasts; hypoxia; lipids; pancreatic cancer; tumor microenvironment; unsaturated fatty acids

DOI:  https://doi.org/10.1016/j.celrep.2024.114972
Cancer Res. 2024 Nov 15.

Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling.

Ziyan Xu, Alexandra Kuhlmann-Hogan, Shihao Xu, Hubert Tseng, Dan Chen, Shirong Tan, Ming Sun, Victoria Tripple, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech.

Tumor-associated macrophages (TAMs) are a heterogenous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment (TME). In this study, we unveiled a mechanism by which scavenger receptor CD36 suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I interferon (IFN-I) production, mirroring the inverse correlation between CD36 and IFN-I response observed in cancer patients. IFN-I, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFN-I signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacological inhibition of CD36 to rejuvenate anti-tumor immunity.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-4027
Eur J Pharmacol. 2024 Nov 09. pii: S0014-2999(24)00811-2. [Epub ahead of print] 177121

Leukemia Inhibitory Factor Receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr-/- mice.

Esmeralda Hemme, Marie A C Depuydt, Peter J van Santbrink, Anouk Wezel, Harm J Smeets, Amanda C Foks, Johan Kuiper, Ilze Bot.

  Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the IL-6 cytokine family, such as Interleukin-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development. Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr-/- mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n=15) or control solvent (n=15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice. Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque.

Keywords:  Adhesion molecules; Atherosclerosis; Cholesterol; Cytokines; Inflammation; leukemia inhibitory factor

DOI:  https://doi.org/10.1016/j.ejphar.2024.177121
Sci Rep. 2024 11 12. 14(1): 27714

ACVR2B polymorphism, Adiponectin, and GDF-15 levels as biomarkers for cachexia in gastrointestinal cancer.

Laura de Martin Coletti, Gabriela Gonzalez Segura, Leticia Cangemi Guedes de Freitas, Jackeline de Souza Rangel Machado, Rene Beleboni, Adilson Faccio, Mozart Marins, Ana Lúcia Fachin.

  Reversing cancer cachexia remains a challenge. Genetic biomarkers for the early detection of the disease have been explored in order to enable the implementation of preventive measures. We therefore genotyped candidate genes based on cachexia phenotype and quantified adiponectin and GDF-15 levels in cachectic patients with gastrointestinal cancer. Patients with a diagnosis of gastrointestinal cancer were divided into a cachectic and a non-cachectic group after the start of chemotherapy. A control group (no cancer) was also included. We genotyped the following single nucleotide polymorphisms (SNPs) by quantitative PCR: FOXO3 (rs1935949), FOXO3 (rs4946935), ACVR2B (rs2268757), and SELP (rs6136). In addition, we quantified adiponectin and GDF-15 levels by ELISA. The rs2268757 SNP in the ACVR2B gene was associated with the weight loss phenotype in cachectic patients with gastrointestinal cancer (non-cachectic, P = 0.004). Plasma adiponectin levels were higher in cachectic patients compared to controls (P = 0.01) and non-cachectic patients (P = 0.004). GDF-15 was also elevated in cachectic patients compared to controls (P < 0.0001) and non-cachectic patients (P = 0.001). Analysis by sex showed elevated adiponectin levels in men (control, P = 0.01) and cachectic women (control, P = 0.04; non-cachectic, P = 0.01), as well as elevated GDF-15 levels in men (control, P = 0.002) and cachectic women (control, P = 0.002; non-cachectic, P = 0.007). However, there was no significant difference in the levels of these cytokines between cachectic men and women. The results suggest the rs2268757 SNP in the ACVR2B gene, adiponectin, and GDF-15 as potential biomarkers of cachexia in gastrointestinal cancer.

Keywords:  Adiponectin; Cachexia; Chemotherapy; Gastrointestinal cancer; Polymorphism

DOI:  https://doi.org/10.1038/s41598-024-79176-7
Cancer Res. 2024 Nov 12.

Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer.

Terrance J Haanen, Sophie Boock, Catherine G Callahan, Irene Peris, Kaitlin P Zawacki, Brynne Raines, Charles A Nino, Brian Tran, Alexis Harold, Gabrielle Hodges Onishi, Matthew Hinderman, Amanda Dowdican, Wei Huang, Derek J Taylor, Sarah E Taylor, Mark W Jackson, Analisa DiFeo, Caitlin M O'Connor, Goutham Narla.

Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer and can drive tumorigenesis and metastasis. Elucidation of the mechanisms by which PP2A-Aα mutants promote tumor development and progression could help identify therapeutic opportunities. Here, we showed that expression of these mutants in USC/UCS cell-lines enhanced tumor-initiating capacity, drove a hybrid epithelial-to-mesenchymal (EM) plasticity phenotype, and elevated secretion of the tumorigenic cytokine IGFBP2. Therapeutic targeting of the IGFBP2/IGF1R signaling axis using small molecules and genetic approaches resulted in marked tumor growth inhibition. Mechanistically, PP2A regulated IGFBP2 expression through the transcription factor, NF-κB, which harbors a B56 recognition motif. Collectively, these results identify a role for PP2A in regulating paracrine cancer cell signaling that can be targeted to block the initiation and metastasis of high-grade uterine cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1263
Res Sports Med. 2024 Nov 14. 1-10

Change in interleukin (IL)-6, 8, and 10 and its association with an increase in core temperature following a 7-mile running race in the warm weather.

Yasuki Sekiguchi, Yuri Hosokawa, Ekow Dadzie, Virgilio Lopez, Joseph J Bivona, Staci N Thornton, John F Jardine, Douglas J Casa, Elaine C Lee.

  The purposes of this study were 1) to investigate if cytokines were increased following a running road-race, and 2) to examine associations between cytokines and hyperthermia. Seventy-seven recreational runners participated in this study which occurred at the 7-mile race in the heat (ambient temperature, 25.0-26.7°C; %RH, 56.7-79.0 ± 5.0%). Before and following the race, blood draws were performed to measure circulating inflammatory cytokines. Core temperature was measured using an ingestible thermistor throughout the race. Core temperature was significantly higher at post-race (39.5 ± 0.7°C) than pre-race (36.9 ± 0.4°C, p < 0.001). IL-6, IL-8, and IL-10 significantly increased at post-race (IL-6, 48.0 ± 22.3 pg⋅ml-1; IL-8, 63.8 ± 23.9 pg⋅ml-1; IL-10, 29.2 ± 20.0 pg⋅ml-1) compared to pre-race (IL-6, 28.4 ± 13.6 pg⋅ml-1; IL-8, 53.2 ± 19.4 pg⋅ml-1; IL-10, 18.6 ± 11.9 pg⋅ml-1, p < 0.001). A greater increase in core temperature pre- to post-race was predicted by the faster finish time, a greater increase in IL-6, and greater body mass loss during the race (r2 = 0.298, p < 0.001). Small associations were found between IL-8 and core temperature at post-race (r = 0.255, p = 0.025). In conclusion, cytokines concentrations and core temperature increased following the race. Moreover, post-race hyperthermia is associated with increased IL-6, faster finish times, and higher body mass losses.

Keywords:  Immune system; exercise heat stress; heat exposure

DOI:  https://doi.org/10.1080/15438627.2024.2428602
Cell. 2024 Nov 07. pii: S0092-8674(24)01214-5. [Epub ahead of print]

A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.

Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long.

  β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.

Keywords:  BHB; enzyme; ketone; metabolite; metabolomics; obesity

DOI:  https://doi.org/10.1016/j.cell.2024.10.032