bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2023‒10‒22
nine papers selected by
Alex Muir, University of Chicago
  1. Cancer Metabolism under Limiting Oxygen Conditions.
  2. Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function.
  3. Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
  4. Arginine Promotes Metabolic Reprogramming and Liver Tumorigenesis.
  5. Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.
  6. Metabolic advantages of regulatory T cells dictated by cancer cells.
  7. Metabolic control of cancer metastasis: role of amino acids at secondary organ sites.
  8. Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses.
  9. CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.
  1. Cold Spring Harb Perspect Med. 2023 Oct 17. pii: a041542. [Epub ahead of print]
    Cancer Metabolism under Limiting Oxygen Conditions.
    Laura C Kim, Nicholas P Lesner, M Celeste Simon.
      Molecular oxygen (O2) is essential for cellular bioenergetics and numerous biochemical reactions necessary for life. Solid tumors outgrow the native blood supply and diffusion limits of O2, and therefore must engage hypoxia response pathways that evolved to withstand acute periods of low O2 Hypoxia activates coordinated gene expression programs, primarily through hypoxia inducible factors (HIFs), to support survival. Many of these changes involve metabolic rewiring such as increasing glycolysis to support ATP generation while suppressing mitochondrial metabolism. Since low O2 is often coupled with nutrient stress in the tumor microenvironment, other responses to hypoxia include activation of nutrient uptake pathways, metabolite scavenging, and regulation of stress and growth signaling cascades. Continued development of models that better recapitulate tumors and their microenvironments will lead to greater understanding of oxygen-dependent metabolic reprogramming and lead to more effective cancer therapies.
    DOI:  https://doi.org/10.1101/cshperspect.a041542
  2. Curr Opin Biotechnol. 2023 Oct 18. pii: S0958-1669(23)00118-0. [Epub ahead of print]84 103008
    Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function.
    Helena B Madsen, Marlies Jw Peeters, Per Thor Straten, Claus Desler.
      Nucleotide metabolism plays a crucial role in the regulation of the tumor microenvironment (TME) and immune cell function. In the TME, limited availability of nucleotide precursors due to increased consumption by tumor cells and T cells affects both tumor development and immune function. Metabolic reprogramming in tumor cells favors pathways supporting growth and proliferation, including nucleotide synthesis. Additionally, extracellular nucleotides, such as ATP and adenosine, exhibit dual roles in modulating immune function and tumor cell survival. ATP stimulates antitumor immunity by activating purinergic receptors, while adenosine acts as a potent immunosuppressor. Targeting nucleotide metabolism in the TME holds immense promise for cancer therapy. Understanding the intricate relationship between nucleotide metabolism, the TME, and immune responses will pave the way for innovative therapeutic interventions.
    DOI:  https://doi.org/10.1016/j.copbio.2023.103008
  3. Cancer Metab. 2023 Oct 19. 11(1): 18
    Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
    Amy K Holt, Arafath K Najumudeen, Tracey J Collard, Hao Li, Laura M Millett, Ashley J Hoskin, Danny N Legge, Eleanor M H Mortensson, Dustin J Flanagan, Nicholas Jones, Madhu Kollareddy, Penny Timms, Matthew D Hitchings, James Cronin, Owen J Sansom, Ann C Williams, Emma E Vincent.
      BACKGROUND: To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.METHODS: We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.
    RESULTS: We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor-CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.
    CONCLUSIONS: Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.
    Keywords:  Aspirin; CB-839; Colorectal cancer; Glutaminase; Metabolic reprogramming; Metabolism
    DOI:  https://doi.org/10.1186/s40170-023-00318-y
  4. Cancer Discov. 2023 Oct 20. OF1
    Arginine Promotes Metabolic Reprogramming and Liver Tumorigenesis.
      Arginine is high in hepatocellular carcinoma and promotes tumorigenesis by altering metabolic gene expression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-166
  5. Cancer Cell. 2023 Oct 16. pii: S1535-6108(23)00328-8. [Epub ahead of print]
    Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.
    Lauren E Colbert, Molly B El Alam, Rui Wang, Tatiana Karpinets, David Lo, Erica J Lynn, Timothy A Harris, Jacob H Elnaggar, Kyoko Yoshida-Court, Katarina Tomasic, Julianna K Bronk, Julie Sammouri, Ananta V Yanamandra, Adilene V Olvera, Lily G Carlin, Travis Sims, Andrea Y Delgado Medrano, Tatiana Cisneros Napravnik, Madison O'Hara, Daniel Lin, Chike O Abana, Hannah X Li, Patricia J Eifel, Anuja Jhingran, Melissa Joyner, Lilie Lin, Lois M Ramondetta, Andrew M Futreal, Kathleen M Schmeler, Geena Mathew, Stephanie Dorta-Estremera, Jianhua Zhang, Xiaogang Wu, Nadim J Ajami, Matthew Wong, Cullen Taniguchi, Joseph F Petrosino, K Jagannadha Sastry, Pablo C Okhuysen, Sara A Martinez, Lin Tan, Iqbal Mahmud, Philip L Lorenzi, Jennifer A Wargo, Ann H Klopp.
      Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.
    Keywords:  cervical cancer; chemoradiation; lactate; metabolism; microbiome; radiation
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.012
  6. Int Immunol. 2023 Oct 14. pii: dxad035. [Epub ahead of print]
    Metabolic advantages of regulatory T cells dictated by cancer cells.
    Masaki Kondo, Shogo Kumagai, Hiroyoshi Nishikawa.
      Cancer cells employ glycolysis for their survival and growth (the 'Warburg effect'). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop 'immune metabolism-based precision medicine'.
    Keywords:  metabolism; regulatory T cell
    DOI:  https://doi.org/10.1093/intimm/dxad035
  7. Oncogene. 2023 Oct 18.
    Metabolic control of cancer metastasis: role of amino acids at secondary organ sites.
    Breelyn Karno, Deanna N Edwards, Jin Chen.
      Most cancer-related deaths are caused by the metastases, which commonly develop at multiple organ sites including the brain, bone, and lungs. Despite longstanding observations that the spread of cancer is not random, our understanding of the mechanisms that underlie metastatic spread to specific organs remains limited. However, metabolism has recently emerged as an important contributor to metastasis. Amino acids are a significant nutrient source to cancer cells and their metabolism which can serve to fuel biosynthetic pathways capable of facilitating cell survival and tumor expansion while also defending against oxidative stress. Compared to the primary tumor, each of the common metastatic sites exhibit vastly different nutrient compositions and environmental stressors, necessitating the need of cancer cells to metabolically thrive in their new environment during colonization and outgrowth. This review seeks to summarize the current literature on amino acid metabolism pathways that support metastasis to common secondary sites, including impacts on immune responses. Understanding the role of amino acids in secondary organ sites may offer opportunities for therapeutic inhibition of cancer metastasis.
    DOI:  https://doi.org/10.1038/s41388-023-02868-3
  8. Cell Metab. 2023 Oct 15. pii: S1550-4131(23)00367-4. [Epub ahead of print]
    Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses.
    Yuerong Zhang, Xiaoyan Yu, Rujuan Bao, Haiyan Huang, Chuanjia Gu, Qianming Lv, Qiaoqiao Han, Xian Du, Xu-Yun Zhao, Youqiong Ye, Ren Zhao, Jiayuan Sun, Qiang Zou.
      Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates adipocyte-derived leptin production in an mTORC1-dependent manner, thereby triggering leptin-boosted antitumor CD8+ T cell responses. Importantly, high plasma leptin levels are correlated with elevated plasma fructose concentrations and improved antitumor CD8+ T cell responses in patients with lung cancer. Our study characterizes a critical role for dietary fructose in shaping adipocyte metabolism to prime antitumor CD8+ T cell responses and highlights that the fructose-leptin axis may be harnessed for cancer immunotherapy.
    Keywords:  adipocyte metabolism; antitumor CD8(+) T cell responses; dietary fructose; mTORC1
    DOI:  https://doi.org/10.1016/j.cmet.2023.09.011
  9. Cell Metab. 2023 Oct 10. pii: S1550-4131(23)00368-6. [Epub ahead of print]
    CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.
    Alexander R Terry, Veronique Nogueira, Hyunsoo Rho, Gopalakrishnan Ramakrishnan, Jing Li, Soeun Kang, Koralege C Pathmasiri, Sameer Ahmed Bhat, Liping Jiang, Shafi Kuchay, Stephanie M Cologna, Nissim Hay.
      A high-fat diet (HFD) promotes metastasis through increased uptake of saturated fatty acids (SFAs). The fatty acid transporter CD36 has been implicated in this process, but a detailed understanding of CD36 function is lacking. During matrix detachment, endoplasmic reticulum (ER) stress reduces SCD1 protein, resulting in increased lipid saturation. Subsequently, CD36 is induced in a p38- and AMPK-dependent manner to promote preferential uptake of monounsaturated fatty acids (MUFAs), thereby maintaining a balance between SFAs and MUFAs. In attached cells, CD36 palmitoylation is required for MUFA uptake and protection from palmitate-induced lipotoxicity. In breast cancer mouse models, CD36-deficiency induced ER stress while diminishing the pro-metastatic effect of HFD, and only a palmitoylation-proficient CD36 rescued this effect. Finally, AMPK-deficient tumors have reduced CD36 expression and are metastatically impaired, but ectopic CD36 expression restores their metastatic potential. Our results suggest that, rather than facilitating HFD-driven tumorigenesis, CD36 plays a supportive role by preventing SFA-induced lipotoxicity.
    Keywords:  CD36; cancer metabolism; fatty acids; matrix detachment; metastasis; palmitoylation
    DOI:  https://doi.org/10.1016/j.cmet.2023.09.012
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