bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–10–22
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Cancer Metabolism under Limiting Oxygen Conditions.
  2. Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function.
  3. Metabolic advantages of regulatory T cells dictated by cancer cells.
  4. MERCI Predicts Mitochondrial Transfer from T Cells to Tumor Cells.
  5. Unlocking the potential of the tumor microenvironment for cancer therapy.
  6. Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.
  7. Metabolic remodeling in astrocytes: Paving the path to brain tumor development.
  8. Tumor-intrinsic metabolic reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment.
  9. Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses.
  10. Prognostic features of the tumor microenvironment in high-grade serous ovarian cancer and dietary immunomodulation.
  11. Single-cell landscape and spatial transcriptomic analysis reveals macrophage infiltration and glycolytic metabolism in kidney renal clear cell carcinoma.
  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. 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
  4. Cancer Discov. 2023 Oct 20. OF1
    MERCI Predicts Mitochondrial Transfer from T Cells to Tumor Cells.
      The developed single-cell method MERCI predicts mitochondrial trafficking between tumor and T cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-168
  5. Pathol Res Pract. 2023 Oct 04. pii: S0344-0338(23)00547-2. [Epub ahead of print]251 154846
    Unlocking the potential of the tumor microenvironment for cancer therapy.
    Muhammad Tufail.
      The tumor microenvironment (TME) holds a crucial role in the progression of cancer. Epithelial-derived tumors share common traits in shaping the TME. The Warburg effect is a notable phenomenon wherein tumor cells exhibit resistance to apoptosis and an increased reliance on anaerobic glycolysis for energy production. Recognizing the pivotal role of the TME in controlling tumor growth and influencing responses to chemotherapy, researchers have focused on developing potential cancer treatment strategies. A wide array of therapies, including immunotherapies, antiangiogenic agents, interventions targeting cancer-associated fibroblasts (CAF), and therapies directed at the extracellular matrix, have been under investigation and have demonstrated efficacy. Additionally, innovative techniques such as tumor tissue explants, "tumor-on-a-chip" models, and multicellular tumor spheres have been explored in laboratory research. This comprehensive review aims to provide insights into the intricate cross-talk between cancer-associated signaling pathways and the TME in cancer progression, current therapeutic approaches targeting the TME, the immune landscape within solid tumors, the role of the viral TME, and cancer cell metabolism.
    Keywords:  Cancer cell metabolism; Solid tumors microenvironment; Targeting the tumor microenvironment; Tumor landscape; Tumor mechanics; Viral induced tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2023.154846
  6. 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
  7. Neurobiol Dis. 2023 Oct 13. pii: S0969-9961(23)00343-1. [Epub ahead of print] 106327
    Metabolic remodeling in astrocytes: Paving the path to brain tumor development.
    Myriam Jaraíz-Rodríguez, Lucia Del Prado, Eduardo Balsa.
      The brain is a highly metabolic organ, composed of multiple cell classes, that controls crucial functions of the body. Although neurons have traditionally been the main protagonist, astrocytes have gained significant attention over the last decade. In this regard, astrocytes are a type of glial cells that have recently emerged as critical regulators of central nervous system (CNS) function and play a significant role in maintaining brain energy metabolism. However, in certain scenarios, astrocyte behavior can go awry, which poses a significant threat to brain integrity and function. This is definitively the case for mutations that turn normal astrocytes and astrocytic precursors into gliomas, an aggressive type of brain tumor. In addition, healthy astrocytes can interact with tumor cells, becoming part of the tumor microenvironment and influencing disease progression. In this review, we discuss the recent evidence suggesting that disturbed metabolism in astrocytes can contribute to the development and progression of fatal human diseases such as cancer. Emphasis is placed on detailing the molecular bases and metabolic pathways of this disease and highlighting unique metabolic vulnerabilities that can potentially be exploited to develop successful therapeutic opportunities.
    Keywords:  Astrocytes; Astrocytoma; Cancer; Glioma; Metabolism
    DOI:  https://doi.org/10.1016/j.nbd.2023.106327
  8. Cancer Drug Resist. 2023 ;6(3): 611-641
    Tumor-intrinsic metabolic reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment.
    Kyra Laubach, Tolga Turan, Rebecca Mathew, Julie Wilsbacher, John Engelhardt, Josue Samayoa.
      The development of immune checkpoint blockade (ICB) therapies has been instrumental in advancing the field of immunotherapy. Despite the prominence of these treatments, many patients exhibit primary or acquired resistance, rendering them ineffective. For example, anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed cell death ligand 1 (anti-PD-L1) treatments are widely utilized across a range of cancer indications, but the response rate is only 10%-30%. As such, it is necessary for researchers to identify targets and develop drugs that can be used in combination with existing ICB therapies to overcome resistance. The intersection of cancer, metabolism, and the immune system has gained considerable traction in recent years as a way to comprehensively study the mechanisms that drive oncogenesis, immune evasion, and immunotherapy resistance. As a result, new research is continuously emerging in support of targeting metabolic pathways as an adjuvant to ICB to boost patient response and overcome resistance. Due to the plethora of studies in recent years highlighting this notion, this review will integrate the relevant articles that demonstrate how tumor-derived alterations in energy, amino acid, and lipid metabolism dysregulate anti-tumor immune responses and drive resistance to anti-PD-1/PD-L1 therapy.
    Keywords:  Immunotherapy resistance; amino acid metabolism; energy metabolism; immune checkpoint blockade; lipid metabolism; tumor-immune microenvironment
    DOI:  https://doi.org/10.20517/cdr.2023.60
  9. 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
  10. Life Sci. 2023 Oct 14. pii: S0024-3205(23)00813-5. [Epub ahead of print]333 122178
    Prognostic features of the tumor microenvironment in high-grade serous ovarian cancer and dietary immunomodulation.
    Nathalie D McKenzie, Sarfraz Ahmad, Ahmad Awada, Theresa M Kuhn, Fernando O Recio, Robert W Holloway.
      High-grade serous ovarian cancer (HGSOC) is a particularly lethal malignancy that is prognostically influenced by the immune profile of the tumor microenvironment (TME). TME immune profiles have been sub-categorized according to features associated with both survival outcomes as well as response to systemic therapies. Five suggested immune phenotypes have been described and correlated with overall survival outcomes. Phenotypes associated with shorter overall survival rates appear to have prominent immunosuppressive features within their TME. The opportunity to triage patients according to their prognostic TME profile might allow selection of individual patients with poor prognostic features who could most benefit from innovative immunomodulatory treatment strategies. Two potential strategies to indirectly manipulate the TME (and oncologic outcomes) are alteration of the gut microbiome composition and alteration of TME metabolism through dietary interventions. Experimental dietary modifications in humans designed for influencing cancer outcomes are only beginning to be studied in a prospective fashion. Herein we summarize prognostic TME features in HGSOC and potential opportunities for immunomodulation via dietary and gut microbial interventions.
    Keywords:  Immunomodulation; Ovarian cancer; Prognosis; Treatment response; Tumor metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.lfs.2023.122178
  11. Aging (Albany NY). 2023 Oct 16. 15
    Single-cell landscape and spatial transcriptomic analysis reveals macrophage infiltration and glycolytic metabolism in kidney renal clear cell carcinoma.
    Chen-Yueh Wen, Jui-Hu Hsiao, Yen-Dun Tony Tzeng, Renin Chang, Yi-Ling Tsang, Chen-Hsin Kuo, Chia-Jung Li.
      The present study investigates the clinical relevance of glycolytic factors, specifically PGAM1, in the tumor microenvironment of kidney renal clear cell carcinoma (KIRC). Despite the established role of glycolytic metabolism in cancer pathophysiology, the prognostic implications and key targets in KIRC remain elusive. We analyzed GEO and TCGA datasets to identify DEGs in KIRC and studied their relationship with immune gene expression, survival, tumor stage, gene mutations, and infiltrating immune cells. We explored Pgam1 gene expression in different kidney regions using spatial transcriptomics after mouse kidney injury analysis. Single-cell RNA-sequencing was used to assess the association of PGAM1 with immune cells. Findings were validated with tumor specimens from 60 KIRC patients, correlating PGAM1 expression with clinicopathological features and prognosis using bioinformatics and immunohistochemistry. We demonstrated the expression of central gene regulators in renal cancer in relation to genetic variants, deletions, and tumor microenvironment. Mutations in these hub genes were positively associated with distinct immune cells in six different immune datasets and played a crucial role in immune cell infiltration in KIRC. Single-cell RNA-sequencing revealed that elevated PGAM1 was associated with immune cell infiltration, specifically macrophages. Furthermore, pharmacogenomic analysis of renal cancer cell lines indicated that inactivation of PGAM1 was associated with increased sensitivity to specific small-molecule drugs. Altered PGAM1 in KIRC is associated with disease progression and immune microenvironment. It has diagnostic and prognostic implications, indicating its potential in precision medicine and drug screening.
    Keywords:  PGAM1; glycolytic metabolism; immune infiltration; kidney renal clear cell carcinoma; single cell-RNA sequencing
    DOI:  https://doi.org/10.18632/aging.205128
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