bims-stacyt 2022-11-20 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2022–11–20
thirteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Metabolic reprogramming in the immunosuppression of tumor-associated macrophages.
PERK/ATF4-dependent expression of the stress response protein REDD1 promotes pro-inflammatory cytokine expression in the heart of obese mice.
Essential roles of the cytokine oncostatin M in crosstalk between muscle fibers and immune cells in skeletal muscle after aerobic exercise.
MEK1-dependent MondoA phosphorylation regulates glucose uptake in response to ketone bodies in colorectal cancer cells.
An mTORC1 to HRI signaling axis promotes cytotoxicity of proteasome inhibitors in multiple myeloma.
Interleukin 6 receptor is not directly involved in regulation of body weight in diet-induced obesity with and without physical exercise.
Pan-cancer analysis of tissue and single-cell HIF-pathway activation using a conserved gene signature.
Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex.
Ribosome stalling is a signal for metabolic regulation by the ribotoxic stress response.
Diabetic hyperglycemia promotes primary tumor progression through glycation-induced tumor extracellular matrix stiffening.
Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.
Suppression of CCL2 angiocrine function by adrenomedullin promotes tumor growth.
The NLRP3 inflammasome: regulation by metabolic signals.

Chin Med J (Engl). 2022 Nov 17.

Metabolic reprogramming in the immunosuppression of tumor-associated macrophages.

Ying Wang, Dan Wang, Li Yang, Yi Zhang.

ABSTRACT: Tumor-associated macrophages (TAMs) are an essential proportion of tumor-infiltrating immune cells in the tumor microenvironment (TME) and have immunosuppressive functions. The high plasticity and corresponding phenotypic transformation of TAMs facilitate oncogenesis and progression, and suppress antineoplastic responses. Due to the uncontrolled proliferation of tumor cells, metabolism homeostasis is regulated, leading to a series of alterations in the metabolite profiles in the TME, which have a commensurate influence on immune cells. Metabolic reprogramming of the TME has a profound impact on the polarization and function of TAMs, and can alter their metabolic profiles. TAMs undergo a series of metabolic reprogramming processes, involving glucose, lipid, and amino acid metabolism, and other metabolic pathways, which terminally promote the development of the immunosuppressive phenotype. TAMs express a pro-tumor phenotype by increasing glycolysis, fatty acid oxidation, cholesterol efflux, and arginine, tryptophan, glutamate, and glutamine metabolism. Previous studies on the metabolism of TAMs demonstrated that metabolic reprogramming has intimate crosstalk with anti-tumor or pro-tumor phenotypes and is crucial for the function of TAMs themselves. Targeting metabolism-related pathways is emerging as a promising therapeutic modality because of the massive metabolic remodeling that occurs in malignant cells and TAMs. Evidence reveals that the efficacy of immune checkpoint inhibitors is improved when combined with therapeutic strategies targeting metabolism-related pathways. In-depth research on metabolic reprogramming and potential therapeutic targets provides more options for anti-tumor treatment and creates new directions for the development of new immunotherapy methods. In this review, we elucidate the metabolic reprogramming of TAMs and explore how they sustain immunosuppressive phenotypes to provide a perspective for potential metabolic therapies.

DOI: https://doi.org/10.1097/CM9.0000000000002426
Am J Physiol Endocrinol Metab. 2022 Nov 16.

PERK/ATF4-dependent expression of the stress response protein REDD1 promotes pro-inflammatory cytokine expression in the heart of obese mice.

Shaunaci A Stevens, Maria K Gonzalez Aguiar, Allyson L Toro, Esma I Yerlikaya, Siddharth Sunilkumar, Ashley M VanCleave, Jessica Pfleger, Elisa A Bradley, Scot R Kimball, Michael D Dennis.

  Endoplasmic reticulum (ER) stress and inflammation are hallmarks of myocardial impairment. Here we investigated a role for the stress response protein REDD1 as a molecular link between ER stress and inflammation in cardiomyocytes. In mice fed a high-fat high-sucrose (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 weeks, REDD1 expression in the heart was increased in coordination with markers of ER stress and inflammation. In human AC16 cardiomyocytes exposed to either hyperglycemic conditions or the saturated fatty acid palmitate, REDD1 expression was increased coincident with ER stress and upregulated expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNF⍺. In cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions, pharmacological inhibition of the ER kinase PERK or knockdown of the transcription factor ATF4 prevented the increase in REDD1 expression. REDD1 deletion reduced pro-inflammatory cytokine expression in both cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions and in the hearts of obese mice. Overall, the findings support a model wherein HFHS diet contributes to the development of inflammation in cardiomyocytes by promoting REDD1 expression via activation of a PERK/ATF4 signaling axis.

Keywords:  DDIT4; ER stress; diabetes; inflammation; obesity

DOI:  https://doi.org/10.1152/ajpendo.00238.2022
J Biol Chem. 2022 Nov 09. pii: S0021-9258(22)01129-2. [Epub ahead of print] 102686

Essential roles of the cytokine oncostatin M in crosstalk between muscle fibers and immune cells in skeletal muscle after aerobic exercise.

Tadasuke Komori, Yoshihiro Morikawa.

  Crosstalk between muscle fibers and immune cells is well known in the processes of muscle repair after exercise, especially resistance exercise. In aerobic exercise, however, this crosstalk is not fully understood. In the present study, we found that macrophages, especially anti-inflammatory (M2) macrophages, and neutrophils accumulated in skeletal muscles of mice 24 h after a single bout of an aerobic exercise. The expression of oncostatin M (OSM), a member of the IL-6 family of cytokines, was also increased in muscle fibers immediately after the exercise. Additionally, we determined that deficiency of OSM in mice inhibited the exercise-induced accumulation of M2 macrophages and neutrophils, while intramuscular injection of OSM increased these immune cells in skeletal muscles. Furthermore, the chemokines related to the recruitment of macrophages and neutrophils were induced in skeletal muscles after aerobic exercise, which were attenuated in OSM-deficient mice. Among them, CC chemokine ligand (CCL) 2, CCL7, and CXC chemokine ligand (CXCL) 1 were induced by OSM in skeletal muscles. Next, we analyzed the direct effects of OSM on the skeletal muscle macrophages, because the OSM receptor β subunit was expressed predominantly in macrophages in the skeletal muscle. OSM directly induced the expression of these chemokines and anti-inflammatory markers in the skeletal muscle macrophages. From these findings, we conclude that OSM is essential for aerobic exercise-induced accumulation of M2 macrophages and neutrophils in the skeletal muscle partly through the regulation of chemokine expression in macrophages.

Keywords:  chemokine; cytokine; exercise; macrophage; neutrophil; skeletal muscle

DOI:  https://doi.org/10.1016/j.jbc.2022.102686
Cancer Sci. 2022 Nov 18.

MEK1-dependent MondoA phosphorylation regulates glucose uptake in response to ketone bodies in colorectal cancer cells.

Yemin Zhu, Nannan Xu, Siming Wu, Yu Luan, Huiyi Ke, Lifang Wu, Yakui Li, Ying Lu, Xindan Xing, Na Tian, Qi Liu, Lingfeng Tong, Lei Hu, Yingning Ji, Zhangbing Chen, Ping Zhang, Xuemei Tong.

  The Mondo family transcription factor MondoA plays a pivotal role in sensing metabolites, such as glucose, glutamine and lactic acid, to regulate glucose metabolism and cell proliferation. Ketone bodies are important signals for reducing glucose uptake. However, it is unclear whether MondoA functions in ketone body-regulated glucose transport. Here we reported that ketone bodies promoted MondoA nuclear translocation and binding to the promoter of its target gene TXNIP. Ketone bodies reduced glucose uptake, increased apoptosis and decreased proliferation of colorectal cancer cells, which was impeded by MondoA knockdown. Moreover, we identified MEK1 as a novel component of the MondoA protein complex using a proteomic approach. Mechanistically, MEK1 interacted with MondoA and enhanced tyrosine 222, but not serine or threonine, phosphorylation of MondoA, inhibiting MondoA nuclear translocation and transcriptional activity. Ketone bodies decreased MEK1-dependent MondoA phosphorylation by blocking MondoA and MEK1 interaction, leading to MondoA nuclear translocation, TXNIP transcription and inhibition of glucose uptake. Therefore, our study has not only demonstrated that ketone bodies reduce glucose uptake, promote apoptosis and inhibit cell proliferation in colorectal cancer cells by regulating MondoA phosphorylation, but also identified MEK1-dependent phosphorylation as a new mechanism to manipulate MondoA activity.

Keywords:  MondoA; glucose uptake; ketone bodies; phosphorylation; proliferation

DOI:  https://doi.org/10.1111/cas.15667
Cell Death Dis. 2022 Nov 18. 13(11): 969

An mTORC1 to HRI signaling axis promotes cytotoxicity of proteasome inhibitors in multiple myeloma.

Odai Darawshi, Barbara Muz, Shiri Gershon Naamat, Bellam Praveen, Mohamed Mahameed, Karin Goldberg, Priya Dipta, Miriam Shmuel, Francesca Forno, Shatha Boukeileh, Hadas Pahima, Julia Hermann, Marc S Raab, Alexandra M Poos, Niels Weinhold, Chaggai Rosenbluh, Moshe E Gatt, Wilhelm Palm, Abdel Kareem Azab, Boaz Tirosh.

Multiple myeloma (MM) causes approximately 20% of deaths from blood cancers. Notwithstanding significant therapeutic progress, such as with proteasome inhibitors (PIs), MM remains incurable due to the development of resistance. mTORC1 is a key metabolic regulator, which frequently becomes dysregulated in cancer. While mTORC1 inhibitors reduce MM viability and synergize with other therapies in vitro, clinically, mTORC1 inhibitors are not effective for MM. Here we show that the inactivation of mTORC1 is an intrinsic response of MM to PI treatment. Genetically enforced hyperactivation of mTORC1 in MM was sufficient to compromise tumorigenicity in mice. In vitro, mTORC1-hyperactivated MM cells gained sensitivity to PIs and hypoxia. This was accompanied by increased mitochondrial stress and activation of the eIF2α kinase HRI, which initiates the integrated stress response. Deletion of HRI elevated the toxicity of PIs in wt and mTORC1-activated MM. Finally, we identified the drug PMA as a robust inducer of mTORC1 activity, which synergized with PIs in inducing MM cell death. These results help explain the clinical inefficacy of mTORC1 inhibitors in MM. Our data implicate mTORC1 induction and/or HRI inhibition as pharmacological strategies to enhance MM therapy by PIs.

DOI: https://doi.org/10.1038/s41419-022-05421-4
Front Endocrinol (Lausanne). 2022 ;13 1028808

Interleukin 6 receptor is not directly involved in regulation of body weight in diet-induced obesity with and without physical exercise.

Anna Rita Minafra, Alexandra Chadt, Puyan Rafii, Hadi Al-Hasani, Kristina Behnke, Jürgen Scheller.

  High level of interleukin 6 (IL-6), released by adipocytes in an obesity-induced, low grade inflammation state, is a regulator of insulin resistance and glucose tolerance. IL-6 has also regenerative, anti-inflammatory and anti-diabetogenic functions, when secreted as myokine by skeletal muscles during physical exercise. IL-6 mainly activates cells via two different receptor constellations: classic and trans-signalling, in which IL-6 initially binds to membrane-bound receptor (IL-6R) or soluble IL-6 receptor (sIL-6R) before activating signal transducing gp130 receptor. Previously, we generated transgenic soluble IL-6 receptor +/+ (sIL-6R+/+) mice with a strategy that mimics ADAM10/17 hyperactivation, reflecting a situation in which only IL-6 trans-signalling is active, whereas classic signalling is completely abrogated. In this study, we metabolically phenotyped IL-6R deficient mice (IL-6R-KO), sIL-6R+/+ mice and wild-type littermates fed either a standard chow (SD) or a high-fat diet (HFD) in combination with a 6-weeks treadmill exercise protocol. All mice were subjected to analyses of body weight and body composition, determination of blood glucose and insulin level under fasting conditions, as well as determination of substrate preference by indirect calorimetry. Neither classic IL-6 nor trans-signalling do influence the outcome of diet-induced obesity, insulin sensitivity and glycaemic control. Furthermore, IL-6R deficiency is not impairing the beneficial effect of physical exercise. We conclude that the IL-6R does not play a requisite role in regulation of body weight and glucose metabolism in diet-induced obese mice.

Keywords:  diet; exercise; interleukin 6 (IL-6); mouse model; obesity

DOI:  https://doi.org/10.3389/fendo.2022.1028808
Cell Rep. 2022 Nov 15. pii: S2211-1247(22)01523-6. [Epub ahead of print]41(7): 111652

Pan-cancer analysis of tissue and single-cell HIF-pathway activation using a conserved gene signature.

Olivia Lombardi, Ran Li, Silvia Halim, Hani Choudhry, Peter J Ratcliffe, David R Mole.

  Activation of cellular hypoxia pathways, orchestrated by HIF (hypoxia-inducible factor) transcription factors, is a common feature of multiple tumor types, resulting from microenvironment factors and oncogenic mutation. Although they help drive many of the "hallmarks" of cancer and are associated with poor outcome and resistance to therapy, the transcriptional targets of HIF vary considerably depending on the cell type. By integrating 72 genome-wide assays of HIF binding and transcriptional regulation from multiple cancer types, we define a consensus set of 48 HIF target genes that is highly conserved across cancer types and cell lineages. These genes provide an effective marker of HIF activation in bulk and single-cell transcriptomic analyses across a wide range of cancer types and in malignant and stromal cell types. This allows the tissue-orchestrated responses to the hypoxic tumor microenvironment and to oncogenic HIF activation to be deconvoluted at the tumor and single-cell level.

Keywords:  CP: cancer; HIF; VHL; cancer; gene signature; hypoxia; oxygen-sensing; single-cell; transcription; transcriptomics; tumorigenesis

DOI:  https://doi.org/10.1016/j.celrep.2022.111652
iScience. 2022 Nov 18. 25(11): 105458

Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex.

Molly C McNamara, Aaron M Hosios, Margaret E Torrence, Ting Zhao, Cameron Fraser, Meghan Wilkinson, David J Kwiatkowski, Elizabeth P Henske, Chin-Lee Wu, Kristopher A Sarosiek, Alexander J Valvezan, Brendan D Manning.

  mTORC1 is aberrantly activated in cancer and in the genetic tumor syndrome tuberous sclerosis complex (TSC), which is caused by loss-of-function mutations in the TSC complex, a negative regulator of mTORC1. Clinically approved mTORC1 inhibitors, such as rapamycin, elicit a cytostatic effect that fails to eliminate tumors and is rapidly reversible. We sought to determine the effects of mTORC1 on the core regulators of intrinsic apoptosis. In TSC2-deficient cells and tumors, we find that mTORC1 inhibitors shift cellular dependence from MCL-1 to BCL-2 and BCL-XL for survival, thereby altering susceptibility to BH3 mimetics that target specific pro-survival BCL-2 proteins. The BCL-2/BCL-XL inhibitor ABT-263 synergizes with rapamycin to induce apoptosis in TSC-deficient cells and in a mouse tumor model of TSC, resulting in a more complete and durable response. These data expose a therapeutic vulnerability in regulation of the apoptotic machinery downstream of mTORC1 that promotes a cytotoxic response to rapamycin.

Keywords:  Biological sciences; Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2022.105458
Cell Metab. 2022 Nov 08. pii: S1550-4131(22)00489-2. [Epub ahead of print]

Ribosome stalling is a signal for metabolic regulation by the ribotoxic stress response.

Goda Snieckute, Aitana Victoria Genzor, Anna Constance Vind, Laura Ryder, Mark Stoneley, Sébastien Chamois, René Dreos, Cathrine Nordgaard, Frederike Sass, Melanie Blasius, Aida Rodríguez López, Sólveig Hlín Brynjólfsdóttir, Kasper Langebjerg Andersen, Anne E Willis, Lisa B Frankel, Steen Seier Poulsen, David Gatfield, Zachary Gerhart-Hines, Christoffer Clemmensen, Simon Bekker-Jensen.

  Impairment of translation can lead to collisions of ribosomes, which constitute an activation platform for several ribosomal stress-surveillance pathways. Among these is the ribotoxic stress response (RSR), where ribosomal sensing by the MAP3K ZAKα leads to activation of p38 and JNK kinases. Despite these insights, the physiological ramifications of ribosomal impairment and downstream RSR signaling remain elusive. Here, we show that stalling of ribosomes is sufficient to activate ZAKα. In response to amino acid deprivation and full nutrient starvation, RSR impacts on the ensuing metabolic responses in cells, nematodes, and mice. The RSR-regulated responses in these model systems include regulation of AMPK and mTOR signaling, survival under starvation conditions, stress hormone production, and regulation of blood sugar control. In addition, ZAK-/- male mice present a lean phenotype. Our work highlights impaired ribosomes as metabolic signals and demonstrates a role for RSR signaling in metabolic regulation.

Keywords:  AMPK; FGF21; ZAK-alpha; amino acid starvation; mTOR; metabolic regulation; mouse models; ribosome collision; ribotoxic stress response

DOI:  https://doi.org/10.1016/j.cmet.2022.10.011
Sci Adv. 2022 Nov 16. 8(46): eabo1673

Diabetic hyperglycemia promotes primary tumor progression through glycation-induced tumor extracellular matrix stiffening.

Wenjun Wang, Lauren A Hapach, Lauren Griggs, Kyra Smart, Yusheng Wu, Paul V Taufalele, Matthew M Rowe, Katherine M Young, Madison E Bates, Andrew C Johnson, Nicholas J Ferrell, Ambra Pozzi, Cynthia A Reinhart-King.

Diabetes mellitus is a complex metabolic disorder that is associated with an increased risk of breast cancer. Despite this correlation, the interplay between tumor progression and diabetes, particularly with regard to stiffening of the extracellular matrix, is still mechanistically unclear. Here, we established a murine model where hyperglycemia was induced before breast tumor development. Using the murine model, in vitro systems, and patient samples, we show that hyperglycemia increases tumor growth, extracellular matrix stiffness, glycation, and epithelial-mesenchymal transition of tumor cells. Upon inhibition of glycation or mechanotransduction in diabetic mice, these same metrics are reduced to levels comparable with nondiabetic tumors. Together, our study describes a novel biomechanical mechanism by which diabetic hyperglycemia promotes breast tumor progression via glycating the extracellular matrix. In addition, our work provides evidence that glycation inhibition is a potential adjuvant therapy for diabetic cancer patients due to the key role of matrix stiffening in both diseases.

DOI: https://doi.org/10.1126/sciadv.abo1673
Sci Rep. 2022 Nov 16. 12(1): 19660

Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.

Kavita Ramji, Tomasz M Grzywa, Anna Sosnowska, Aleksandra Paterek, Marta Okninska, Zofia Pilch, Joanna Barankiewicz, Filip Garbicz, Katarzyna Borg, Urszula Bany-Laszewicz, Abdesamad Zerrouqi, Beata Pyrzynska, Anna Rodziewicz-Lurzynska, Diana Papiernik, Piotr Sklepkiewicz, Hanna Kedzierska, Adam Staruch, Radoslaw Sadowski, Olga Ciepiela, Ewa Lech-Maranda, Przemyslaw Juszczynski, Urszula Mackiewicz, Michal Maczewski, Dominika Nowis, Jakub Golab.

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.

DOI: https://doi.org/10.1038/s41598-022-24137-1
J Exp Med. 2023 Jan 02. pii: e20211628. [Epub ahead of print]220(1):

Suppression of CCL2 angiocrine function by adrenomedullin promotes tumor growth.

Akiko Nakayama, Kenneth Anthony Roquid, András Iring, Boris Strilic, Stefan Günther, Min Chen, Lee S Weinstein, Stefan Offermanns.

Within the tumor microenvironment, tumor cells and endothelial cells regulate each other. While tumor cells induce angiogenic responses in endothelial cells, endothelial cells release angiocrine factors, which act on tumor cells and other stromal cells. We report that tumor cell-derived adrenomedullin has a pro-angiogenic as well as a direct tumor-promoting effect, and that endothelium-derived CC chemokine ligand 2 (CCL2) suppresses adrenomedullin-induced tumor cell proliferation. Loss of the endothelial adrenomedullin receptor CALCRL or of the G-protein Gs reduced endothelial proliferation. Surprisingly, tumor cell proliferation was also reduced after endothelial deletion of CALCRL or Gs. We identified CCL2 as a critical angiocrine factor whose formation is inhibited by adrenomedullin. Furthermore, CCL2 inhibited adrenomedullin formation in tumor cells through its receptor CCR2. Consistently, loss of endothelial CCL2 or tumor cell CCR2 normalized the reduced tumor growth seen in mice lacking endothelial CALCRL or Gs. Our findings show tumor-promoting roles of adrenomedullin and identify CCL2 as an angiocrine factor controlling adrenomedullin formation by tumor cells.

DOI: https://doi.org/10.1084/jem.20211628
Trends Immunol. 2022 Nov 09. pii: S1471-4906(22)00211-3. [Epub ahead of print]

The NLRP3 inflammasome: regulation by metabolic signals.

Antoni Olona, Stuart Leishman, Paras K Anand.

  Macrophages undergo profound metabolic reprogramming upon sensing infectious and sterile stimuli. This metabolic shift supports and regulates essential innate immune functions, including activation of the NLRP3 inflammasome. Within distinct metabolic networks, key enzymes play pivotal roles to control flux restraining detrimental inflammasome signaling. However, depending on the metabolic cues, specific enzymes and metabolites result in inflammasome activation outcomes which contrast other metabolic steps in the pathway. We posit that understanding which metabolic steps commit to discrete inflammasome fates will broaden our understanding of metabolic checkpoints to maintain homeostasis and offer better therapeutic options in human disease.

Keywords:  NLRP3; TCA cycle; glycolysis; inflammasome; lipids; metabolism

DOI:  https://doi.org/10.1016/j.it.2022.10.003