bims-mecami 2024-01-14 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–01–14
ten papers selected by
Oltea Sampetrean, Keio University

Immunosurveillance encounters cancer metabolism.
Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities.
Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment.
Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.
Recreating metabolic interactions of the tumour microenvironment.
Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses.
Modulating ferroptosis sensitivity: environmental and cellular targets within the tumor microenvironment.
A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.
Deficiency of TOP1MT enhances glycolysis through the stimulation of PDK4 expression in gastric cancer.
The immune system and metabolic products in epilepsy and glioma-associated epilepsy: emerging therapeutic directions.

EMBO Rep. 2024 Jan 12.

Immunosurveillance encounters cancer metabolism.

Yu-Ming Chuang, Sheue-Fen Tzeng, Ping-Chih Ho, Chin-Hsien Tsai.

  Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.

Keywords:  Cancer Evolution; Immunoediting; Immunometabolism

DOI:  https://doi.org/10.1038/s44319-023-00038-w
Biomark Res. 2024 Jan 07. 12(1): 1

Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities.

Yujing Qian, Yujia Yin, Xiaocui Zheng, Zhaoyuan Liu, Xipeng Wang.

  Tumor-associated macrophages (TAMs) are a heterogeneous population that play diverse functions in tumors. Their identity is determined not only by intrinsic factors, such as origins and transcription factors, but also by external signals from the tumor microenvironment (TME), such as inflammatory signals and metabolic reprogramming. Metabolic reprogramming has rendered TAM to exhibit a spectrum of activities ranging from pro-tumorigenic to anti-tumorigenic, closely associated with tumor progression and clinical prognosis. This review implicates the diversity of TAM phenotypes and functions, how this heterogeneity has been re-evaluated with the advent of single-cell technologies, and the impact of TME metabolic reprogramming on TAMs. We also review current therapies targeting TAM metabolism and offer new insights for TAM-dependent anti-tumor immunotherapy by focusing on the critical role of different metabolic programs in TAMs.

Keywords:  Immunotherapy; Metabolic reprogramming; Single-cell omics; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s40364-023-00549-7
Nat Commun. 2024 Jan 11. 15(1): 451

Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment.

Matteo Villa, David E Sanin, Petya Apostolova, Mauro Corrado, Agnieszka M Kabat, Carmine Cristinzio, Annamaria Regina, Gustavo E Carrizo, Nisha Rana, Michal A Stanczak, Francesc Baixauli, Katarzyna M Grzes, Jovana Cupovic, Francesca Solagna, Alexandra Hackl, Anna-Maria Globig, Fabian Hässler, Daniel J Puleston, Beth Kelly, Nina Cabezas-Wallscheid, Peter Hasselblatt, Bertram Bengsch, Robert Zeiser, Sagar, Joerg M Buescher, Edward J Pearce, Erika L Pearce.

Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8+ T cell pool. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.

DOI: https://doi.org/10.1038/s41467-024-44689-2
bioRxiv. 2023 Dec 24. pii: 2023.12.24.573250. [Epub ahead of print]

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

Keene L Abbott, Ahmed Ali, Bradley I Reinfeld, Amy Deik, Sonu Subudhi, Madelyn D Landis, Rachel A Hongo, Kirsten L Young, Tenzin Kunchok, Christopher S Nabel, Kayla D Crowder, Johnathan R Kent, Maria Lucia L Madariaga, Rakesh K Jain, Kathryn E Beckermann, Caroline A Lewis, Clary B Clish, Alexander Muir, W Kimryn Rathmell, Jeffrey C Rathmell, Matthew G Vander Heiden.

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer driven tissue factors in shaping nutrient availability in these tumors.

DOI: https://doi.org/10.1101/2023.12.24.573250
Trends Endocrinol Metab. 2024 Jan 10. pii: S1043-2760(23)00250-3. [Epub ahead of print]

Recreating metabolic interactions of the tumour microenvironment.

Rodrigo Curvello, Nikolaus Berndt, Sandra Hauser, Daniela Loessner.

  Tumours are heterogeneous tissues containing diverse populations of cells and an abundant extracellular matrix (ECM). This tumour microenvironment prompts cancer cells to adapt their metabolism to survive and grow. Besides epigenetic factors, the metabolism of cancer cells is shaped by crosstalk with stromal cells and extracellular components. To date, most experimental models neglect the complexity of the tumour microenvironment and its relevance in regulating the dynamics of the metabolism in cancer. We discuss emerging strategies to model cellular and extracellular aspects of cancer metabolism. We highlight cancer models based on bioengineering, animal, and mathematical approaches to recreate cell-cell and cell-matrix interactions and patient-specific metabolism. Combining these approaches will improve our understanding of cancer metabolism and support the development of metabolism-targeting therapies.

Keywords:  cancer metabolism; cancer models; mathematical models; tumour microenvironment

DOI:  https://doi.org/10.1016/j.tem.2023.12.005
Cold Spring Harb Perspect Med. 2024 Jan 08. pii: a041411. [Epub ahead of print]

Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses.

Kathleen M McAndrews, Krishnan K Mahadevan, Raghu Kalluri.

The tumor microenvironment (TME) is a complex ecosystem of both cellular and noncellular components that functions to impact the evolution of cancer. Various aspects of the TME have been targeted for the control of cancer; however, TME composition is dynamic, with the overall abundance of immune cells, endothelial cells (ECs), fibroblasts, and extracellular matrix (ECM) as well as subsets of TME components changing at different stages of progression and in response to therapy. To effectively treat cancer, an understanding of the functional role of the TME is needed. Genetically engineered mouse models have enabled comprehensive insight into the complex interactions within the TME ecosystem that regulate disease progression. Here, we review recent advances in mouse models that have been employed to understand how the TME regulates cancer initiation, progression, metastasis, and response to therapy.

DOI: https://doi.org/10.1101/cshperspect.a041411
J Exp Clin Cancer Res. 2024 Jan 13. 43(1): 19

Modulating ferroptosis sensitivity: environmental and cellular targets within the tumor microenvironment.

Yuze Hua, Sen Yang, Yalu Zhang, Jiayi Li, Mengyi Wang, Palashate Yeerkenbieke, Quan Liao, Qiaofei Liu.

  Ferroptosis, a novel form of cell death triggered by iron-dependent phospholipid peroxidation, presents significant therapeutic potential across diverse cancer types. Central to cellular metabolism, the metabolic pathways associated with ferroptosis are discernible in both cancerous and immune cells. This review begins by delving into the intricate reciprocal regulation of ferroptosis between cancer and immune cells. It subsequently details how factors within the tumor microenvironment (TME) such as nutrient scarcity, hypoxia, and cellular density modulate ferroptosis sensitivity. We conclude by offering a comprehensive examination of distinct immunophenotypes and environmental and metabolic targets geared towards enhancing ferroptosis responsiveness within the TME. In sum, tailoring precise ferroptosis interventions and combination strategies to suit the unique TME of specific cancers may herald improved patient outcomes.

Keywords:  Cellular metabolism; Ferroptosis; Tumor Microenvironment; Tumor immunity

DOI:  https://doi.org/10.1186/s13046-023-02925-5
Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01034-1. [Epub ahead of print]

A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Xu Wang, Sheng-Qiao Fu, Xiao Yuan, Feng Yu, Qian Ji, Hao-Wen Tang, Rong-Kun Li, Shan Huang, Pei-Qi Huang, Wei-Ting Qin, Hao Zuo, Chang Du, Lin-Li Yao, Hui Li, Jun Li, Dong-Xue Li, Yan Yang, Shu-Yu Xiao, Aziguli Tulamaiti, Xue-Feng Wang, Chun-Hua Dai, Xu Zhang, Shu-Heng Jiang, Li-Peng Hu, Xue-Li Zhang, Zhi-Gang Zhang.

  Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Keywords:  5-HT; CD8(+) T cell; GAPDH; glycolysis; post-translational modification; serotonin; serotonylation; tumor immunity

DOI:  https://doi.org/10.1016/j.molcel.2023.12.015
Cancer Metab. 2024 Jan 10. 12(1): 2

Deficiency of TOP1MT enhances glycolysis through the stimulation of PDK4 expression in gastric cancer.

Hongqiang Wang, Xutao Sun, Chen Yang, Ziqi Li, Danwen Jin, Wenwen Zhu, Ze Yu.

   BACKGROUND: Abnormal glucose metabolism is one of the determinants of maintaining malignant characteristics of cancer. Targeting cancer metabolism is regarded as a new strategy for cancer treatment. Our previous studies have found that TOP1MT is a crucial gene that inhibits glycolysis and cell metastasis of gastric cancer (GC) cells, but the mechanism of its regulation of glycolysis remains unclear.
METHODS: Transcriptome sequencing data, clinic-pathologic features of GC from a variety of public databases, and WGCNA were used to identify novel targets of TOP1MT. Immunohistochemical results of 250 patients with GC were used to analyze the relative expression relationship between TOP1MT and PDK4. The function of TOP1MT was investigated by migration assays and sea-horse analysis in vitro.
RESULTS: We discovered a mitochondrial topoisomerase I, TOP1MT, which correlated with a higher risk of metastasis. Functional experiments revealed that TOP1MT deficiency promotes cell migration and glycolysis through increasing PDK4 expression. Additionally, the stimulating effect of TOP1MT on glycolysis may be effectively reversed by PDK4 inhibitor M77976.
CONCLUSIONS: In brief, our work demonstrated the critical function of TOP1MT in the regulation of glycolysis by PDK4 in gastric cancer. Inhibiting glycolysis and limiting tumor metastasis in GC may be accomplished by suppressing PDK4.

Keywords:  Cell migration; Gastric cancer; Glycolysis; PDK4; TOP1MT

DOI:  https://doi.org/10.1186/s40170-024-00330-w
JCI Insight. 2024 Jan 09. pii: e174753. [Epub ahead of print]9(1):

The immune system and metabolic products in epilepsy and glioma-associated epilepsy: emerging therapeutic directions.

Shashwat Tripathi, Cody L Nathan, Matthew C Tate, Craig M Horbinski, Jessica W Templer, Joshua M Rosenow, Timothy L Sita, Charles D James, Benjamin Deneen, Stephen D Miller, Amy B Heimberger.

Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are nonresponsive to medical treatment. Nearly all currently approved ASMs target neuronal activity through ion channel modulation. Recent human and animal model studies have implicated new immunotherapeutic and metabolomic approaches that may benefit patients with epilepsy. In this Review, we detail the proinflammatory immune landscape of epilepsy and contrast this with the immunosuppressive microenvironment in patients with glioma-related epilepsy. In the tumor setting, excessive neuronal activity facilitates immunosuppression, thereby contributing to subsequent glioma progression. Metabolic modulation of the IDH1-mutant pathway provides a dual pathway for reversing immune suppression and dampening seizure activity. Elucidating the relationship between neurons and immunoreactivity is an area for the prioritization and development of the next era of ASMs.

DOI: https://doi.org/10.1172/jci.insight.174753