bims-stacyt 2021-10-24 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2021–10–24
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.
Lactate in the tumour microenvironment: From immune modulation to therapy.
The impact of hypoxia on immune state in cancer.
ERK5 modulates IL-6 secretion and contributes to tumor-induced immune suppression.
Low glycaemic diets alter lipid metabolism to influence tumour growth.
Multi‑faceted role of cancer‑associated adipocytes in the tumor microenvironment (Review).
Tumor-Released Products Promote Bone Marrow-Derived Macrophage Survival and Proliferation.
STAT3 Mediated Regulation of Glucose Metabolism in Leukemia Cells.
Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward.

Nat Immunol. 2021 Oct 22.

Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.

Giusy Di Conza, Chin-Hsien Tsai, Hector Gallart-Ayala, Yi-Ru Yu, Fabien Franco, Lea Zaffalon, Xin Xie, Xiaoyun Li, Zhengtao Xiao, Lydia N Raines, Maryline Falquet, Antoine Jalil, Jason W Locasale, Piergiorgio Percipalle, David Masson, Stanley Ching-Cheng Huang, Fabio Martinon, Julijana Ivanisevic, Ping-Chih Ho.

Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.

DOI: https://doi.org/10.1038/s41590-021-01047-4
EBioMedicine. 2021 Oct 13. pii: S2352-3964(21)00420-5. [Epub ahead of print]73 103627

Lactate in the tumour microenvironment: From immune modulation to therapy.

Zi-Hao Wang, Wen-Bei Peng, Pei Zhang, Xiang-Ping Yang, Qiong Zhou.

  Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity.

Keywords:  Cancer immunity; Cancer metabolism; Glycolytic enzymes; Lactate; Monocarboxylate transporters; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.ebiom.2021.103627
Life Sci. 2021 Oct 15. pii: S0024-3205(21)01044-4. [Epub ahead of print] 120057

The impact of hypoxia on immune state in cancer.

Keywan Mortezaee, Jamal Majidpoor.

  Hypoxia is a known feature of solid tumors and a critical promoter of tumor hallmarks. Hypoxia influences tumor immunity in a way favoring immune evasion and resistance. Extreme hypoxia and aberrant hypoxia-inducible factor-1 (HIF-1) activity in tumor microenvironment (TME) is a drawback for effective immunotherapy. Infiltration and activity of CD8+ T cells is reduced in such condition, whereas regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) show high activities. Highly hypoxic TME also impairs maturation and activity of dendritic cell (DCs) and natural killer (NK) cells. In addition, the hypoxic TME positively is linked positively with metabolic changes in cells of immune system. These alterations are indicative of a need for hypoxia modulation as a complementary targeting strategy to go with immune checkpoint inhibitor (ICI) therapy.

Keywords:  CD8(+) T cell; Dendritic cell (DC); Hypoxia; Hypoxia inducible factor (HIF); Immune checkpoint inhibitor (ICI); Natural killer (NK); Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.lfs.2021.120057
Cell Death Dis. 2021 Oct 20. 12(11): 969

ERK5 modulates IL-6 secretion and contributes to tumor-induced immune suppression.

Kristina Riegel, Hajime Yurugi, Janine Schlöder, Helmut Jonuleit, Manuel Kaulich, Friederike Kirschner, Danielle Arnold-Schild, Stefan Tenzer, Hansjörg Schild, Krishnaraj Rajalingam.

Tumors exhibit a variety of strategies to dampen antitumor immune responses. With an aim to identify factors that are secreted from tumor cells, we performed an unbiased mass spectrometry-based secretome analysis in lung cancer cells. Interleukin-6 (IL-6) has been identified as a prominent factor secreted by tumor cells and cancer-associated fibroblasts isolated from cancer patients. Incubation of dendritic cell (DC) cultures with tumor cell supernatants inhibited the production of IL-12p70 in DCs but not the surface expression of other activation markers which is reversed by treatment with IL-6 antibody. Defects in IL-12p70 production in the DCs inhibited the differentiation of Th1 but not Th2 and Th17 cells from naïve CD4+ T cells. We also demonstrate that the classical mitogen-activated protein kinase, ERK5/MAPK7, is required for IL-6 production in tumor cells. Inhibition of ERK5 activity or depletion of ERK5 prevented IL-6 production in tumor cells, which could be exploited for enhancing antitumor immune responses.

DOI: https://doi.org/10.1038/s41419-021-04257-8
Nature. 2021 Oct 20.

Low glycaemic diets alter lipid metabolism to influence tumour growth.

Evan C Lien, Anna M Westermark, Yin Zhang, Chen Yuan, Zhaoqi Li, Allison N Lau, Kiera M Sapp, Brian M Wolpin, Matthew G Vander Heiden.

Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth1-5. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels6-8, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth.

DOI: https://doi.org/10.1038/s41586-021-04049-2
Mol Med Rep. 2021 Dec;pii: 866. [Epub ahead of print]24(6):

Multi‑faceted role of cancer‑associated adipocytes in the tumor microenvironment (Review).

Huihui Yao, Songbing He.

  Adipocytes are a type of stromal cell found in numerous different tissues that serve an active role in the tumor microenvironment. Cancer‑associated adipocytes (CAAs) display a malignant phenotype and are found at the invasive tumor front, which mediates the crosstalk network between adipocytes (the precursor cells that will become cancer‑associated adipocytes in the future) and cancer cells. The present review covers the mechanisms of adipocytes in the development of cancer, including metabolic reprogramming, chemotherapy resistance and adipokine regulation. Furthermore, the potential mechanisms involved in the adipocyte‑cancer cell cycle in various types of cancer, including breast, ovarian, colon and rectal cancer, are discussed. Deciphering the complex network of CAA‑cancer cell crosstalk will provide insights into tumor biology and optimize therapeutic strategies.

Keywords:  CAA; TME; adipokines; chemotherapy resistance; metabolic reprogramming

DOI:  https://doi.org/10.3892/mmr.2021.12506
Biomedicines. 2021 Oct 04. pii: 1387. [Epub ahead of print]9(10):

Tumor-Released Products Promote Bone Marrow-Derived Macrophage Survival and Proliferation.

Juliana Maria Motta, Vivian Mary Rumjanek, Alberto Mantovani, Massimo Locati.

  Macrophages play a central role within the tumor microenvironment, with relevant implications for tumor progression. The modulation of their phenotype is one of the mechanisms used by tumors to escape from effective immune responses. This study was designed to analyze the influence of soluble products released by tumors, here represented by the tumor-conditioned media of two tumor cell lines (3LL from Lewis lung carcinoma and MN/MCA from fibrosarcoma), on murine macrophage differentiation and polarization in vitro. Data revealed that tumor-conditioned media stimulated macrophage differentiation but influenced the expression levels of macrophage polarization markers, cytokine production, and microRNAs of relevance for macrophage biology. Interestingly, tumor-derived soluble products supported the survival and proliferation rate of bone marrow precursor cells, an effect observed even with mature macrophages in the presence of M2 but not M1 inducers. Despite presenting low concentrations of macrophage colony-stimulating factor (M-CSF), tumor-conditioned media alone also supported the proliferation of cells to a similar extent as exogenous M-CSF. This effect was only evident in cells positive for the expression of the M-CSF receptor (CD115) and occurred preferentially within the CD16+ subset. Blocking CD115 partially reversed the effect on proliferation. These results suggest that tumors release soluble products that not only promote macrophage development from bone marrow precursors but also stimulate the proliferation of cells with specific phenotypes that could support protumoral functions.

Keywords:  CD115; CD16; arginase-1; macrophage proliferation; tumor-associated macrophages

DOI:  https://doi.org/10.3390/biomedicines9101387
Gene. 2021 Oct 13. pii: S0378-1119(21)00607-7. [Epub ahead of print] 146012

STAT3 Mediated Regulation of Glucose Metabolism in Leukemia Cells.

Burcu Yucel, Sedef Altundağ Kara, Mustafa Baki Cekmen, Saniye Ada, Berna Demırcan Tan.

  Cancer cells rewire metabolic pathways as they demand more ATP and building blocks for proliferation. Glucose is the most consumed nutrient by cancer cells and metabolized to lactate even in the presence of oxygen. This phenomenon is called 'aerobic glycolysis'. Also, glucose level is found lower in tumor environment. Leukemia is characterized by abnormal proliferation of hematopoietic cells. STAT3 a transcription factor and an oncogene is upregulated in many tumor types. Despite its well-defined functions, STAT3 has also been proposed as a metabolic regulator. In this study, we aimed to determine the role STAT3 activation in glucose limitation, in leukemia cell lines. K562, NB-4 and HL-60 cells were found sensitive to glucose limitation. In low glucose conditions, total and nuclear STAT3 protein was decreased in all cells. In mitochondria, S727 phosphorylated STAT3 (mitochondrial form) was determined slightly increased in K562 and NB-4 cells. On the other side, ectopically STAT3 expressing cells had increased glucose consumption and less proliferated in low glucose medium. This data suggests that aerobic glycolysis might be upregulated upon STAT3 expression in leukemia cells, in glucose limitation. Furthermore, in this study, it was found that GLUT3 expressing cells did not reduce STAT3 expression in low glucose medium. GLUT3 was previously determined as a molecular marker for cell sensitivity to glucose limitation, therefore, it could be hypothesized as GLUT3 expressing cells might not need to alter STAT3 expression in low glucose level. Overall, our data suggest that leukemia cells rewire glucose metabolism via STAT3 expression in glucose limitation. Elucidating pathways that cause differential phosphorylation of STAT3 and its interaction with other energy regulating pathways in cellular response to glucose limitation might be beneficial to design new drug targets such as STAT3 inhibitors for leukemia treatment.

Keywords:  GLUT3; Leukemia; STAT3 pS727; STAT3 pY705; glucose metabolism

DOI:  https://doi.org/10.1016/j.gene.2021.146012
J Immunother Cancer. 2021 Oct;pii: e003013. [Epub ahead of print]9(10):

Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward.

Maria Rain Jennings, David Munn, John Blazeck.

  Tumors accumulate metabolites that deactivate infiltrating immune cells and polarize them toward anti-inflammatory phenotypes. We provide a comprehensive review of the complex networks orchestrated by several of the most potent immunosuppressive metabolites, highlighting the impact of adenosine, kynurenines, prostaglandin E2, and norepinephrine and epinephrine, while discussing completed and ongoing clinical efforts to curtail their impact. Retrospective analyses of clinical data have elucidated that their activity is negatively associated with prognosis in diverse cancer indications, though there is a current paucity of approved therapies that disrupt their synthesis or downstream signaling axes. We hypothesize that prior lukewarm results may be attributed to redundancies in each metabolites' synthesis or signaling pathway and highlight routes for how therapeutic development and patient stratification might proceed in the future.

Keywords:  adenosine; immunotherapy; indoleamine-pyrrole 2,3-dioxygenase; metabolic networks and pathways; tumor escape

DOI:  https://doi.org/10.1136/jitc-2021-003013