bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2022‒10‒16
twelve papers selected by
Linda Chan
Yale University
  1. CD8+ T cell metabolic changes in breast cancer.
  2. Metabolic communication in the tumour-immune microenvironment.
  3. d-2HG Inhibits Effector T Cells by Altering Metabolic Programming.
  4. The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression.
  5. SnapShot: Cancer immunoediting.
  6. Targeting metabolic rewiring might decrease spread of tumor cells: Mitochondrial tRNA modifications promote cancer metastasis.
  7. The metabolic plasticity of B cells.
  8. Src: coordinating metabolism in cancer.
  9. Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects.
  10. Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC.
  11. Breast Cancer Metastatic Dormancy and Relapse: An enigma of microenvironment(s).
  12. Reprogramming of cancer-associated fibroblasts by apoptotic cancer cells inhibits lung metastasis via Notch1-WISP-1 signaling.
  1. Biochim Biophys Acta Mol Basis Dis. 2022 Oct 08. pii: S0925-4439(22)00236-8. [Epub ahead of print] 166565
    CD8+ T cell metabolic changes in breast cancer.
    Angela Castoldi, Jennifer Lee, Daniel de Siqueira Carvalho, Fabrício O Souto.
      Immunometabolism has advanced our understanding of how the cellular environment and nutrient availability regulates immune cell fate. Not only are metabolic pathways closely tied to cell signaling and differentiation, but can induce different subsets of immune cells to adopt unique metabolic programs, influencing disease progression. Dysregulation of immune cell metabolism plays an essential role in the progression of several diseases including breast cancer (BC). Metabolic reprogramming plays a critical role in regulating T cell functions. CD8+ T cells are an essential cell type within the tumor microenvironment (TME). To induce antitumor responses, CD8+ T cells need to adapt their metabolism to fulfill their energy requirement for effective function. However, different markers and immunologic techniques have made identifying specific CD8+ T cells subtypes in BC a challenge to the field. This review discusses the immunometabolic processes of CD8+ T cell in the TME in the context of BC and highlights the role of CD8+ T cell metabolic changes in tumor progression.
    Keywords:  Breast cancer; CD8(+) T cells; Immunometabolism; Tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166565
  2. Nat Cell Biol. 2022 Oct 13.
    Metabolic communication in the tumour-immune microenvironment.
    Kung-Chi Kao, Stefania Vilbois, Chin-Hsien Tsai, Ping-Chih Ho.
      The metabolically hostile tumour microenvironment imposes barriers to tumour-infiltrating immune cells and impedes durable clinical remission following immunotherapy. Metabolic communication between cancer cells and their neighbouring immune cells could determine the amplitude and type of immune responses, highlighting a potential involvement of metabolic crosstalk in immune surveillance and escape. In this Review, we explore tumour-immune metabolic crosstalk and discuss potential nutrient-limiting strategies that favour anti-tumour immune responses.
    DOI:  https://doi.org/10.1038/s41556-022-01002-x
  3. Cancer Discov. 2022 Oct 14. OF1
    d-2HG Inhibits Effector T Cells by Altering Metabolic Programming.
      Uptake of the oncometabolite d-2HG impairs the metabolism and effector functions of CD8+ T cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-182
  4. J Clin Invest. 2022 Oct 13. pii: e157302. [Epub ahead of print]
    The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression.
    Kyung Mi Choi, Jeong Jin Kim, Jihye Yoo, Ku Sul Kim, Youngeun Gu, John Eom, Haengdueng Jeong, Kyungeun Kim, Ki Taek Nam, Young Soo Park, Joon-Yong Chung, Jun-Young Seo.
      Metabolic reprogramming is an important cancer hallmark. However, the mechanisms driving metabolic phenotypes of cancer cells are unclear. Here, we showed that the interferon (IFN)-inducible protein, viperin, drives metabolic alteration in cancer cells. Viperin was observed in various types of cancer and inversely correlated with the survival rate of patients with gastric, lung, breast, renal, pancreatic, or brain cancer. By generating viperin knockdown or stably expressing cancer cells, we showed that viperin, but not a mutant lacking its iron-sulfur cluster-binding motif, increased lipogenesis and glycolysis via inhibition of fatty acid β-oxidation in cancer cells. In the tumor microenvironment, deficiency of fatty acids and oxygen as well as production of IFNs upregulated viperin expression via the PI3K/AKT/mTOR/HIF-1α and JAK/STAT pathways. Moreover, viperin was primarily expressed in cancer stem-like cells (CSCs) and functioned to promote metabolic reprogramming and enhance CSC properties, thereby facilitating tumor growth in xenograft mouse models. Collectively, our data indicate that viperin-mediated metabolic alteration drives the metabolic phenotype and progression of cancer.
    Keywords:  Cancer; Fatty acid oxidation; Glucose metabolism; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI157302
  5. Cell. 2022 Oct 13. pii: S0092-8674(22)01199-0. [Epub ahead of print]185(21): 4038-4038.e1
    SnapShot: Cancer immunoediting.
    Siva Karthik Varanasi, Susan M Kaech, Jack D Bui.
      In the tumor microenvironment, immune cells and tumor cells interact in a process called cancer immunoediting, giving rise to changes in gene expression, metabolism, mutational burden, and cellularity in the tumor. This SnapShot compares endogenous versus therapy-induced cancer immunoediting and outlines the molecular and cellular characteristics of interactions that result in complete tumor regression versus tumor escape and progression. To view this SnapShot, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.cell.2022.09.027
  6. Signal Transduct Target Ther. 2022 Oct 08. 7(1): 360
    Targeting metabolic rewiring might decrease spread of tumor cells: Mitochondrial tRNA modifications promote cancer metastasis.
    Maik Luu, Alexander Visekruna.
      
    DOI:  https://doi.org/10.1038/s41392-022-01205-6
  7. Front Mol Biosci. 2022 ;9 991188
    The metabolic plasticity of B cells.
    Yurena Vivas-García, Alejo Efeyan.
      The humoral response requires rapid growth, biosynthetic capacity, proliferation and differentiation of B cells. These processes involve profound B-cell phenotypic transitions that are coupled to drastic changes in metabolism so as to meet the extremely different energetic requirements as B cells switch from resting to an activated, highly proliferative state and to plasma or memory cell fates. Thus, B cells execute a multi-step, energetically dynamic process of profound metabolic rewiring from low ATP production to transient and large increments of energy expenditure that depend on high uptake and consumption of glucose and fatty acids. Such metabolic plasticity is under tight transcriptional and post-transcriptional regulation. Alterations in B-cell metabolism driven by genetic mutations or by extrinsic insults impair B-cell functions and differentiation and may underlie the anomalous behavior of pathological B cells. Herein, we review molecular switches that control B-cell metabolism and fuel utilization, as well as the emerging awareness of the impact of dynamic metabolic adaptations of B cells throughout the different phases of the humoral response.
    Keywords:  B-cell activation; Oxphos; anabolism; glycolysis; humoral response; metabolic plasticity
    DOI:  https://doi.org/10.3389/fmolb.2022.991188
  8. Oncogene. 2022 Oct 10.
    Src: coordinating metabolism in cancer.
    Sara G Pelaz, Arantxa Tabernero.
      Metabolism must be tightly regulated to fulfil the dynamic requirements of cancer cells during proliferation, migration, stemness and differentiation. Src is a node of several signals involved in many of these biological processes, and it is also an important regulator of cell metabolism. Glucose uptake, glycolysis, the pentose-phosphate pathway and oxidative phosphorylation are among the metabolic pathways that can be regulated by Src. Therefore, this oncoprotein is in an excellent position to coordinate and finely tune cell metabolism to fuel the different cancer cell activities. Here, we provide an up-to-date summary of recent progress made in determining the role of Src in glucose metabolism as well as the link of this role with cancer cell metabolic plasticity and tumour progression. We also discuss the opportunities and challenges facing this field.
    DOI:  https://doi.org/10.1038/s41388-022-02487-4
  9. Front Immunol. 2022 ;13 986847
    Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects.
    Xiaojin Feng, Xue Li, Na Liu, Ningning Hou, Xiaodong Sun, Yongping Liu.
      The recent increase in the pathogenesis of autoimmune diseases revealed the critical role of T cells. Investigation into immunometabolism has drawn attention to metabolic processes other than glycometabolism. In rapidly dividing immune cells, including T lymphocytes, the consumption of glutamine is similar to or higher than that of glucose even though glucose is abundant. In addition to contributing to many processes critical for cellular integrity and function, glutamine, as the most abundant amino acid, was recently regarded as an immunomodulatory nutrient. A better understanding of the biological regulation of glutaminolysis in T cells will provide a new perspective for the treatment of autoimmune diseases. In this review, we summarized the current knowledge of glutamine catabolism in CD4+ T-cell subsets of autoimmunity. We also focused on potential treatments targeting glutaminolysis in patients with autoimmune diseases. Knowledge of immunometabolism is constantly evolving, and glutamine metabolism may be a potential therapeutic target for autoimmune disease therapy.
    Keywords:  CD4+ T cells; autoimmune diseases; glutamine; glutaminolysis; immune response
    DOI:  https://doi.org/10.3389/fimmu.2022.986847
  10. Front Oncol. 2022 ;12 993437
    Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC.
    Yixue Xia, Binghong Gao, Xue Zhang.
      Most of the primary hepatocellular carcinoma (HCC) develops from Viral Hepatitis including Hepatitis B virus, Hepatitis C Virus, and Nonalcoholic Steatohepatitis. Herein, T cells play crucial roles combined with chronic inflammation and chronic viral infection. However, T cells are gradually exhausted under chronic antigenic stimulation, which leads to T cell exhaustion in the tumor microenvironment, and the exhaustion is associated with mitochondrial dysfunction in T cells. Meanwhile, mitochondria play a crucial role in altering T cells' metabolism modes to achieve desirable immunological responses, wherein mitochondria maintain quality control (MQC) and promote metabolism regulation in the microenvironment. Although immune checkpoint inhibitors have been widely used in clinical practice, there are some limitations in the therapeutic effect, thus combining immune checkpoint inhibitors with targeting mitochondrial biogenesis may enhance cellular metabolic adaptation and reverse the exhausted state. At present, several studies on mitochondrial quality control in HCC have been reported, however, there are gaps in the regulation of immune cell function by mitochondrial metabolism, particularly the modulating of T cell immune function. Hence, this review summarizes and discusses existing studies on the effects of MQC on T cell populations in liver diseases induced by HCC, it would be clued by mitochondrial quality control events.
    Keywords:  T cells exhaustion; hepatocellular carcinoma (HCC); immune cell; metabolism; mitochondria
    DOI:  https://doi.org/10.3389/fonc.2022.993437
  11. Cancer Res. 2022 Oct 10. pii: CAN-22-1902. [Epub ahead of print]
    Breast Cancer Metastatic Dormancy and Relapse: An enigma of microenvironment(s).
    Islam E Elkholi, Andréane Lalonde, Morag Park, Jean-François Côté.
      Multiple factors act in concert to define the fate of disseminated tumor cells (DTCs) to enter dormancy or develop overt metastases. Here, we review these factors in the context of three stages of the metastatic cascade that impact DTCs. First, cells can be programmed within the primary tumor microenvironment to promote or inhibit dissemination, and the primary tumor can condition a premetastatic niche. Then, cancer cells from the primary tumor spread through hematogenous and lymphatic routes, and the primary tumor sends cues systematically to regulate the fate of DTCs. Finally, DTCs home to their metastatic site, where they are influenced by various organ-specific aspects of the new microenvironment. We discuss these factors in the context of breast cancer, where about one third of patients develop metastatic relapse. Finally, we discuss how the standard-of-care options for breast cancer might affect the fate of DTCs.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1902
  12. Cell Mol Immunol. 2022 Oct 14.
    Reprogramming of cancer-associated fibroblasts by apoptotic cancer cells inhibits lung metastasis via Notch1-WISP-1 signaling.
    Hee Ja Kim, Kyungwon Yang, Kiyoon Kim, Ye-Ji Lee, Sieun Lee, Sung Yong Ahn, Young-Ho Ahn, Jihee Lee Kang.
      The interplay between apoptotic cancer cells and the tumor microenvironment modulates cancer progression and metastasis. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting these events through paracrine communication. Here, we demonstrate that conditioned medium (CM) from lung CAFs exposed to apoptotic cancer cells suppresses TGF-β1-induced migration and invasion of cancer cells and CAFs. Direct exposure of CAFs to apoptotic 344SQ cells (ApoSQ) inhibited CAF migration and invasion and the expression of CAF activation markers. Enhanced secretion of Wnt-induced signaling protein 1 (WISP-1) by CAFs exposed to ApoSQ was required for these antimigratory and anti-invasive effects. Pharmacological inhibition of Notch1 activation or siRNA-mediated Notch1 silencing prevented WISP-1 production by CAFs and reversed the antimigratory and anti-invasive effects. Enhanced expression of the Notch ligand delta-like protein 1 on the surface of ultraviolet-irradiated apoptotic lung cancer cells triggered Notch1-WISP-1 signaling. Phosphatidylserine receptor brain-specific angiogenesis inhibitor 1 (BAI1)-Rac1 signaling, which facilitated efferocytosis by CAFs, participated in crosstalk with Notch1 signaling for optimal production of WISP-1. In addition, a single injection of ApoSQ enhanced WISP-1 production, suppressed the expression of CAF activation markers in isolated Thy1+ CAFs, and inhibited lung metastasis in syngeneic immunocompetent mice via Notch1 signaling. Treatment with CM from CAFs exposed to ApoSQ suppressed tumor growth and lung metastasis, whereas treatment with WISP-1-immunodepleted CM from CAFs exposed to ApoSQ reversed the antitumorigenic and antimetastatic effects. Therefore, treatment with CM from CAFs exposed to apoptotic lung cancer cells could be therapeutically applied to suppress CAF activation, thereby preventing cancer progression and metastasis.
    Keywords:  Apoptotic lung cancer cells; CAFs; Efferocytosis; Invasion; Metastasis; Migration; Notch1; WISP-1
    DOI:  https://doi.org/10.1038/s41423-022-00930-w
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