bims-stacyt 2023-10-29 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–10–29
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Proteomics analysis of C2C12 myotubes treated with atrophy inducing cancer cell-derived factors.
Lysine demethylase 3A in hypoxic macrophages promotes ovarian cancer development through regulation of the vascular endothelial growth factor A/Akt signaling.
Endoplasmic Reticulum Stress Promotes the Expression of TNF-α in THP-1 Cells by Mechanisms Involving ROS/CHOP/HIF-1α and MAPK/NF-κB Pathways.
KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.
The Significance of Microenvironmental and Circulating Lactate in Breast Cancer.
The role of extracellular vesicles in skeletal muscle wasting.
MCT4 blockade increases the efficacy of immune checkpoint blockade.
The glucose transporter 2 regulates CD8+ T cell function via environment sensing.
Loss of Anti-Tumor Efficacy by Polyamine Blocking Therapy in GCN2 Null Mice.

Proteomics. 2023 Oct 26. e2300020

Proteomics analysis of C2C12 myotubes treated with atrophy inducing cancer cell-derived factors.

Akbar L Marzan, Sai V Chitti, Sriram Gummadi, Taeyoung Kang, Ching-Seng Ang, Suresh Mathivanan.

  Cancer-associated cachexia is a wasting syndrome that results in dramatic loss of whole-body weight, predominantly due to loss of skeletal muscle mass. It has been established that cachexia inducing cancer cells secrete proteins and extracellular vesicles (EVs) that can induce muscle atrophy. Though several studies examined these cancer-cell derived factors, targeting some of these components have shown little or no clinical benefit. To develop new therapies, understanding of the dysregulated proteins and signaling pathways that regulate catabolic gene expression during muscle wasting is essential. Here, we sought to examine the effect of conditioned media (CM) that contain secreted factors and EVs from cachexia inducing C26 colon cancer cells on C2C12 myotubes using mass spectrometry-based label-free quantitative proteomics. We identified significant changes in the protein profile of C2C12 cells upon exposure to C26-derived CM. Functional enrichment analysis revealed enrichment of proteins associated with inflammation, mitochondrial dysfunction, muscle catabolism, ROS production, and ER stress in CM treated myotubes. Furthermore, strong downregulation in muscle structural integrity and development and/or regenerative pathways were observed. Together, these enriched proteins in atrophied muscle could be utilized as potential muscle wasting markers and the dysregulated biological processes could be employed for therapeutic benefit in cancer-induced muscle wasting.

Keywords:  C26 colon carcinoma; C2C12 myotubes; cancer-associated cachexia; impaired myogenesis; muscle atrophy

DOI:  https://doi.org/10.1002/pmic.202300020
Tissue Cell. 2023 Oct 20. pii: S0040-8166(23)00241-0. [Epub ahead of print]85 102253

Lysine demethylase 3A in hypoxic macrophages promotes ovarian cancer development through regulation of the vascular endothelial growth factor A/Akt signaling.

Yan Song, Liming Li, Yan Xi.

   BACKGROUND: Hypoxia is a vital feature of the tumor microenvironment of OC. Previous evidence exposes that tumor-associated macrophages (TAMs) are connected with the development of ovarian cancer (OC), whereas the accurate regulatory mechanism of hypoxic macrophages regulating tumor advancement remains unclear. Herein, we examined whether the lysine demethylase 3 A (KDM3A) in hypoxic macrophages expedited the development of OC cells.
METHODS: The contents of hypoxia inducible factor-1α (HIF-1α), CD163, CD80, KDM3A, and p-Akt/Akt were detected by western blot. Genomic Spatial Event 4630, Molecular Signatures Database, and Comparative Toxicogenomics Database were utilized for correlated gene prediction. The OC cells viability was scrutinized by cell counting kit-8 assay. The cell proliferation was inspected by 5-Ethynyl-2'-deoxyuridine assay. The vascular endothelial growth factor A (VEGF) level was detected by Enzyme-linked immunosorbent assay.
RESULTS: M2 polarization of TAMs was associated with poor prognosis in sufferers with OC. The OC sufferers with high level of CD163 or low level of CD80 were linked with poor overall survival and disease specific survival. Hypoxia induced THP-1-derived macrophages M2 polarization. KDM3A was high-expressed in hypoxia induced macrophages. Upregulated KDM3A in hypoxic macrophages facilitated OC cell proliferation. KDM3A upregulation in hypoxic macrophages stimulated Akt signaling activation in OC cells. KDM3A in hypoxic macrophages promoted VEGF secretion to activate Akt signaling in OC cells. VEGF inhibition or Akt signaling inactivation reversed the effects of KDM3A in hypoxic macrophages on OC cells viability and proliferation.
CONCLUSION: The KDM3A content and M2 polarization were enhanced in hypoxic macrophages, and KDM3A in hypoxic macrophages promoted OC development through regulation of the VEGF/Akt signaling pathway.

Keywords:  Akt; Hypoxia; Lysine demethylase 3A; Macrophages; Vascular endothelial growth factor A

DOI:  https://doi.org/10.1016/j.tice.2023.102253
Int J Mol Sci. 2023 Oct 14. pii: 15186. [Epub ahead of print]24(20):

Endoplasmic Reticulum Stress Promotes the Expression of TNF-α in THP-1 Cells by Mechanisms Involving ROS/CHOP/HIF-1α and MAPK/NF-κB Pathways.

Nadeem Akhter, Ajit Wilson, Hossein Arefanian, Reeby Thomas, Shihab Kochumon, Fatema Al-Rashed, Mohamed Abu-Farha, Ashraf Al-Madhoun, Fahd Al-Mulla, Rasheed Ahmad, Sardar Sindhu.

  Obesity and metabolic syndrome involve chronic low-grade inflammation called metabolic inflammation as well as metabolic derangements from increased endotoxin and free fatty acids. It is debated whether the endoplasmic reticulum (ER) stress in monocytic cells can contribute to amplify metabolic inflammation; if so, by which mechanism(s). To test this, metabolic stress was induced in THP-1 cells and primary human monocytes by treatments with lipopolysaccharide (LPS), palmitic acid (PA), or oleic acid (OA), in the presence or absence of the ER stressor thapsigargin (TG). Gene expression of tumor necrosis factor (TNF)-α and markers of ER/oxidative stress were determined by qRT-PCR, TNF-α protein by ELISA, reactive oxygen species (ROS) by DCFH-DA assay, hypoxia-inducible factor 1-alpha (HIF-1α), p38, extracellular signal-regulated kinase (ERK)-1,2, and nuclear factor kappa B (NF-κB) phosphorylation by immunoblotting, and insulin sensitivity by glucose-uptake assay. Regarding clinical analyses, adipose TNF-α was assessed using qRT-PCR/IHC and plasma TNF-α, high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and oxidized low-density lipoprotein (OX-LDL) via ELISA. We found that the cooperative interaction between metabolic and ER stresses promoted TNF-α, ROS, CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF2) expression (p ≤ 0.0183),. However, glucose uptake was not impaired. TNF-α amplification was dependent on HIF-1α stabilization and p38 MAPK/p65 NF-κB phosphorylation, while the MAPK/NF-κB pathway inhibitors and antioxidants/ROS scavengers such as curcumin, allopurinol, and apocynin attenuated the TNF-α production (p ≤ 0.05). Individuals with obesity displayed increased adipose TNF-α gene/protein expression as well as elevated plasma levels of TNF-α, CRP, MDA, and OX-LDL (p ≤ 0.05). Our findings support a metabolic-ER stress cooperativity model, favoring inflammation by triggering TNF-α production via the ROS/CHOP/HIF-1α and MAPK/NF-κB dependent mechanisms. This study also highlights the therapeutic potential of antioxidants in inflammatory conditions involving metabolic/ER stresses.

Keywords:  CHOP; ER stress; HIF-1α; MAPK/NF-κB; ROS; TNF-α; inflammation; metabolic stress; metabolic syndrome; obesity

DOI:  https://doi.org/10.3390/ijms242015186
Cell Rep. 2023 Oct 25. pii: S2211-1247(23)01307-4. [Epub ahead of print]42(11): 113295

KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.

Anastasia-Maria Zavitsanou, Ray Pillai, Yuan Hao, Warren L Wu, Eric Bartnicki, Triantafyllia Karakousi, Sahith Rajalingam, Alberto Herrera, Angeliki Karatza, Ali Rashidfarrokhi, Sabrina Solis, Metamia Ciampricotti, Anna H Yeaton, Ellie Ivanova, Corrin A Wohlhieter, Terkild B Buus, Makiko Hayashi, Burcu Karadal-Ferrena, Harvey I Pass, John T Poirier, Charles M Rudin, Kwok-Kin Wong, Andre L Moreira, Kamal M Khanna, Aristotelis Tsirigos, Thales Papagiannakopoulos, Sergei B Koralov.

  Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.

Keywords:  CD103 DC; CP: Cancer; CP: Immunology; KEAP1; LUAD; NRF2; NSCLC; T cell; adenocarcinoma; immune surveillance; immunotherapy; lung cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.113295
Int J Mol Sci. 2023 Oct 19. pii: 15369. [Epub ahead of print]24(20):

The Significance of Microenvironmental and Circulating Lactate in Breast Cancer.

Vincenza Frisardi, Simone Canovi, Salvatore Vaccaro, Raffaele Frazzi.

  Lactate represents the main product of pyruvate reduction catalyzed by the lactic dehydrogenase family of enzymes. Cancer cells utilize great quantities of glucose, shifting toward a glycolytic metabolism. With the contribution of tumor stromal cells and under hypoxic conditions, this leads toward the acidification of the extracellular matrix. The ability to shift between different metabolic pathways is a characteristic of breast cancer cells and is associated with an aggressive phenotype. Furthermore, the preliminary scientific evidence concerning the levels of circulating lactate in breast cancer points toward a correlation between hyperlactacidemia and poor prognosis, even though no clear linkage has been demonstrated. Overall, lactate may represent a promising metabolic target that needs to be investigated in breast cancer.

Keywords:  acidosis; aerobic glycolysis; breast cancer; lactate

DOI:  https://doi.org/10.3390/ijms242015369
J Cachexia Sarcopenia Muscle. 2023 Oct 22.

The role of extracellular vesicles in skeletal muscle wasting.

Xiaohui Zhang, Yanxia Zhao, Wei Yan.

  Skeletal muscle wasting is a complicated metabolic syndrome accompanied by multiple diseases ranging from cancer to metabolic disorders and infectious conditions. The loss of muscle mass significantly impairs muscle function, resulting in poor quality of life and high mortality of associated diseases. The fundamental cellular and molecular mechanisms inducing muscle wasting have been well established, and those related pathways can be activated by a variety of extracellular signals, including inflammatory cytokines and catabolic stimuli. As an emerging messenger of cell-to-cell communications, extracellular vesicles (EVs) also get involved in the progression of muscle wasting by transferring bioactive cargoes including various proteins and non-coding RNAs to skeletal muscle. Like a double-edged sword, EVs play either a pro-wasting or anti-wasting role in the progression of muscle wasting, highly dependent on their parental cells as well as the specific type of cargo they encapsulate. This review aims to illustrate the current knowledge about the biological function of EVs cargoes in skeletal muscle wasting. Additionally, the potential therapeutic implications of EVs in the diagnosis and treatment of skeletal muscle wasting are also discussed. Simultaneously, several outstanding questions are included to shed light on future research.

Keywords:  Exosomes; Extracellular vesicles; Muscle wasting; Therapeutic implications

DOI:  https://doi.org/10.1002/jcsm.13364
J Immunother Cancer. 2023 Oct;pii: e007349. [Epub ahead of print]11(10):

MCT4 blockade increases the efficacy of immune checkpoint blockade.

Nathalie Babl, Sonja-Maria Decking, Florian Voll, Michael Althammer, Ada Sala-Hojman, Roberta Ferretti, Clarissa Korf, Christian Schmidl, Lisa Schmidleithner, Benedikt Nerb, Carina Matos, Gudrun E Koehl, Peter Siska, Christina Bruss, Fabian Kellermeier, Katja Dettmer, Peter J Oefner, Marvin Wichland, Ines Ugele, Christopher Bohr, Wolfgang Herr, Shivapriya Ramaswamy, Timo Heinrich, Christian Herhaus, Marina Kreutz, Kathrin Renner.

   BACKGROUND & AIMS: Intratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be prognostic for the survival of patients with rectal cancer, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance.
METHODS: To determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, we examined the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor in a colorectal carcinoma (CRC) tumor spheroid model co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with an antibody against programmed cell death ligand-1(PD-L1).
RESULTS: Inhibition of MCT4 was sufficient to reduce lactate efflux in three-dimensional (3D) CRC spheroids but not in two-dimensional cell-cultures. Co-administration of the MCT4 inhibitor and ICB augmented immune cell infiltration, T-cell function and decreased CRC spheroid viability in a 3D co-culture model of human CRC spheroids with blood leukocytes. Accordingly, combination of MCT4 and ICB increased intratumoral pH, improved leukocyte infiltration and T-cell activation, delayed tumor growth, and prolonged survival in vivo. MCT1 inhibition exerted no further beneficial impact.
CONCLUSIONS: These findings demonstrate that single MCT4 inhibition represents a novel therapeutic approach to reverse lactic-acid driven immunosuppression and might be suitable to improve ICB efficacy.

Keywords:  Drug Therapy, Combination; Immune Checkpoint Inhibitors; Immunologic Surveillance; Lymphocytes, Tumor-Infiltrating; Metabolism; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2023-007349
Nat Metab. 2023 Oct 26.

The glucose transporter 2 regulates CD8+ T cell function via environment sensing.

Hongmei Fu, Juho Vuononvirta, Silvia Fanti, Fabrizia Bonacina, Antonio D'Amati, Guosu Wang, Thanushiyan Poobalasingam, Maria Fankhaenel, Davide Lucchesi, Rachel Coleby, David Tarussio, Bernard Thorens, Robert J Hearnden, M Paula Longhi, Paul Grevitt, Madeeha H Sheikh, Egle Solito, Susana A Godinho, Michele Bombardieri, David M Smith, Dianne Cooper, Asif J Iqbal, Jeffrey C Rathmell, Samuel Schaefer, Valle Morales, Katiuscia Bianchi, Giuseppe Danilo Norata, Federica M Marelli-Berg.

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation.

DOI: https://doi.org/10.1038/s42255-023-00913-9
Biomedicines. 2023 Oct 05. pii: 2703. [Epub ahead of print]11(10):

Loss of Anti-Tumor Efficacy by Polyamine Blocking Therapy in GCN2 Null Mice.

Eric T Alexander, Erin Fahey, Otto Phanstiel, Susan K Gilmour.

  GCN2 is one of the main sensors of amino acid starvation stress, and its activation in the stressful tumor microenvironment plays a crucial role in tumor survival and progression. We hypothesized that elevated polyamine biosynthesis and subsequent depletion of precursor arginine activates GCN2, thus rewiring metabolism to support tumor cell survival and drive myeloid immunosuppressive function. We sought to determine if the anti-tumor efficacy of a polyamine blocking therapy (PBT) may be mediated by its effect on GCN2. Unlike wild-type mice, PBT treatment in GCN2 knockout mice bearing syngeneic B16.F10 or EG7 tumors resulted in no tumor growth inhibition and no changes in the profile of infiltrating tumor immune cells. Studies with murine bone marrow cell cultures showed that increased polyamine metabolism and subsequent arginine depletion and GCN2 activation played an essential role in the generation and cytoprotective autophagy of myeloid derived suppressor cells (MDSCs) as well as the M2 polarization and survival of macrophages, all of which were inhibited by PBT. In all, our data suggest that polyamine-dependent GCN2 signaling in stromal cells promotes tumor growth and the development of the immunosuppressive tumor microenvironment, and that the PBT anti-tumor effect is mediated, at least in part, by targeting GCN2.

Keywords:  GCN2; macrophages; myeloid derived suppressor cells; polyamine blocking therapy; transport inhibitor; α-difluoromethylornithine

DOI:  https://doi.org/10.3390/biomedicines11102703