bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2023–10–15
twelve papers selected by
Alex Muir, University of Chicago
  1. The yin and yang of itaconate metabolism and its impact on the tumor microenvironment.
  2. Acidic extracellular pH drives accumulation of N1-acetylspermidine and recruitment of protumor neutrophils.
  3. Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.
  4. Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.
  5. Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
  6. Glycolysis-cholesterol metabolic axis in immuno-oncology microenvironment: emerging role in immune cells and immunosuppressive signaling.
  7. Targeting the Cancer-Neuronal Crosstalk in the Pancreatic Cancer Microenvironment.
  8. CD8+ T cells in the cancer-immunity cycle.
  9. Arginine reprograms metabolism in liver cancer via RBM39.
  10. Nuclear GRP78 Promotes Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma.
  11. Distinctly altered lipid components in hepatocellular carcinoma relate to impaired T cell-dependent antitumor immunity.
  12. Elevated extracellular inorganic phosphate inhibits ecto-phosphatase activity in breast cancer cells: Regulation by hydrogen peroxide.
  1. Curr Opin Biotechnol. 2023 Oct 06. pii: S0958-1669(23)00106-4. [Epub ahead of print]84 102996
    The yin and yang of itaconate metabolism and its impact on the tumor microenvironment.
    Fangfang Chen, Birte Dowerg, Thekla Cordes.
      The tumor microenvironment (TME) consists of a network of metabolically interconnected tumor and immune cell types. Macrophages influence the metabolic composition within the TME, which directly impacts the metabolic state and drug response of tumors. The accumulation of oncometabolites, such as succinate, fumarate, and 2-hydroxyglutarate, represents metabolic vulnerabilities in cancer that can be targeted therapeutically. Immunometabolites are emerging as metabolic regulators of the TME impacting immune cell functions and cancer cell growth. Here, we discuss recent discoveries on the potential impact of itaconate on the TME. We highlight how itaconate influences metabolic pathways relevant to immune responses and cancer cell proliferation. We also consider the therapeutic implications of manipulating itaconate metabolism as an immunotherapeutic strategy to constrain tumor growth.
    DOI:  https://doi.org/10.1016/j.copbio.2023.102996
  2. PNAS Nexus. 2023 Oct;2(10): pgad306
    Acidic extracellular pH drives accumulation of N1-acetylspermidine and recruitment of protumor neutrophils.
    Miki Kato, Keisuke Maeda, Ryuichi Nakahara, Haruka Hirose, Ayano Kondo, Sho Aki, Maki Sugaya, Sana Hibino, Miyuki Nishida, Manami Hasegawa, Hinano Morita, Ritsuko Ando, Rika Tsuchida, Minoru Yoshida, Tatsuhiko Kodama, Hideyuki Yanai, Teppei Shimamura, Tsuyoshi Osawa.
      An acidic tumor microenvironment plays a critical role in tumor progression. However, understanding of metabolic reprogramming of tumors in response to acidic extracellular pH has remained elusive. Using comprehensive metabolomic analyses, we demonstrated that acidic extracellular pH (pH 6.8) leads to the accumulation of N1-acetylspermidine, a protumor metabolite, through up-regulation of the expression of spermidine/spermine acetyltransferase 1 (SAT1). Inhibition of SAT1 expression suppressed the accumulation of intra- and extracellular N1-acetylspermidine at acidic pH. Conversely, overexpression of SAT1 increased intra- and extracellular N1-acetylspermidine levels, supporting the proposal that SAT1 is responsible for accumulation of N1-acetylspermidine. While inhibition of SAT1 expression only had a minor effect on cancer cell growth in vitro, SAT1 knockdown significantly decreased tumor growth in vivo, supporting a contribution of the SAT1-N1-acetylspermidine axis to protumor immunity. Immune cell profiling revealed that inhibition of SAT1 expression decreased neutrophil recruitment to the tumor, resulting in impaired angiogenesis and tumor growth. We showed that antineutrophil-neutralizing antibodies suppressed growth in control tumors to a similar extent to that seen in SAT1 knockdown tumors in vivo. Further, a SAT1 signature was found to be correlated with poor patient prognosis. Our findings demonstrate that extracellular acidity stimulates recruitment of protumor neutrophils via the SAT1-N1-acetylspermidine axis, which may represent a metabolic target for antitumor immune therapy.
    Keywords:  N1-acetylspermidine; SAT1; acidic extracellular pH; cancer metabolism; neutrophils
    DOI:  https://doi.org/10.1093/pnasnexus/pgad306
  3. Nat Cancer. 2023 Oct 09.
    Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.
    Joel Encarnación-Rosado, Albert S W Sohn, Douglas E Biancur, Elaine Y Lin, Victoria Osorio-Vasquez, Tori Rodrick, Diana González-Baerga, Ende Zhao, Yumi Yokoyama, Diane M Simeone, Drew R Jones, Seth J Parker, Robert Wild, Alec C Kimmelman.
      Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.
    DOI:  https://doi.org/10.1038/s43018-023-00647-3
  4. Nat Cancer. 2023 Oct 09.
    Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.
    Maria Victoria Recouvreux, Shea F Grenier, Yijuan Zhang, Edgar Esparza, Guillem Lambies, Cheska Marie Galapate, Swetha Maganti, Karen Duong-Polk, Deepika Bhullar, Razia Naeem, David A Scott, Andrew M Lowy, Hervé Tiriac, Cosimo Commisso.
      In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.
    DOI:  https://doi.org/10.1038/s43018-023-00649-1
  5. Cancer Cell. 2023 Oct 09. pii: S1535-6108(23)00319-7. [Epub ahead of print]41(10): 1788-1802.e10
    Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
    Hongyi Zhang, Xuexin Yu, Jianfeng Ye, Huiyu Li, Jing Hu, Yuhao Tan, Yan Fang, Esra Akbay, Fulong Yu, Chen Weng, Vijay G Sankaran, Robert M Bachoo, Elizabeth Maher, John Minna, Anli Zhang, Bo Li.
      Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.
    Keywords:  Mitochondrial Transfer; Statistical Deconvolution; T cell dysfunction; Tumor-Immune Interaction; mtDNA sequencing.; single cell genomics
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.003
  6. Cell Biosci. 2023 Oct 13. 13(1): 189
    Glycolysis-cholesterol metabolic axis in immuno-oncology microenvironment: emerging role in immune cells and immunosuppressive signaling.
    Jing Jin, Qijie Zhao, Zhigong Wei, Keliang Chen, Yonglin Su, Xiaolin Hu, Xingchen Peng.
      Cell proliferation and function require nutrients, energy, and biosynthesis activity to duplicate repertoires for each daughter. It is therefore not surprising that tumor microenvironment (TME) metabolic reprogramming primarily orchestrates the interaction between tumor and immune cells. Tumor metabolic reprogramming affords bioenergetic, signaling intermediates, and biosynthesis requirements for both malignant and immune cells. Different immune cell subsets are recruited into the TME, and these manifestations have distinct effects on tumor progression and therapeutic outcomes, especially the mutual contribution of glycolysis and cholesterol metabolism. In particularly, glycolysis-cholesterol metabolic axis interconnection plays a critical role in the TME modulation, and their changes in tumor metabolism appear to be a double-edged sword in regulating various immune cell responses and immunotherapy efficacy. Hence, we discussed the signature manifestation of the glycolysis-cholesterol metabolic axis and its pivotal role in tumor immune regulation. We also highlight how hypothetical combinations of immunotherapy and glycolysis/cholesterol-related metabolic interventions unleash the potential of anti-tumor immunotherapies, as well as developing more effective personalized treatment strategies.
    Keywords:  Glycolysis-Cholesterol Metabolic Axis; Immune Cells; Immunosuppressive; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1186/s13578-023-01138-9
  7. Int J Mol Sci. 2023 Oct 08. pii: 14989. [Epub ahead of print]24(19):
    Targeting the Cancer-Neuronal Crosstalk in the Pancreatic Cancer Microenvironment.
    Ylenia Capodanno, Michael Hirth.
      Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive solid tumors with a dismal prognosis and an increasing incidence. At the time of diagnosis, more than 85% of patients are in an unresectable stage. For these patients, chemotherapy can prolong survival by only a few months. Unfortunately, in recent decades, no groundbreaking therapies have emerged for PDAC, thus raising the question of how to identify novel therapeutic druggable targets to improve prognosis. Recently, the tumor microenvironment and especially its neural component has gained increasing interest in the pancreatic cancer field. A histological hallmark of PDAC is perineural invasion (PNI), whereby cancer cells invade surrounding nerves, providing an alternative route for metastatic spread. The extent of PNI has been positively correlated with early tumor recurrence and reduced overall survival. Multiple studies have shown that mechanisms involved in PNI are also involved in tumor spread and pain generation. Targeting these pathways has shown promising results in alleviating pain and reducing PNI in preclinical models. In this review, we will describe the mechanisms and future treatment strategies to target this mutually trophic interaction between cancer cells to open novel avenues for the treatment of patients diagnosed with PDAC.
    Keywords:  crosstalk; microenvironment; neuron; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3390/ijms241914989
  8. Immunity. 2023 Oct 10. pii: S1074-7613(23)00410-7. [Epub ahead of print]56(10): 2231-2253
    CD8+ T cells in the cancer-immunity cycle.
    Josephine R Giles, Anna-Maria Globig, Susan M Kaech, E John Wherry.
      CD8+ T cells are end effectors of cancer immunity. Most forms of effective cancer immunotherapy involve CD8+ T cell effector function. Here, we review the current understanding of T cell function in cancer, focusing on key CD8+ T cell subtypes and states. We discuss factors that influence CD8+ T cell differentiation and function in cancer through a framework that incorporates the classic three-signal model and a fourth signal-metabolism-and also consider the impact of the tumor microenvironment from a T cell perspective. We argue for the notion of immunotherapies as "pro-drugs" that act to augment or modulate T cells, which ultimately serve as the drug in vivo, and for the importance of overall immune health in cancer treatment and prevention. The progress in understanding T cell function in cancer has and will continue to improve harnessing of the immune system across broader tumor types to benefit more patients.
    Keywords:  CD8 T cells; T cell exhaustion; cancer; immune checkpoint blockade; immunology; immunotherapy; metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2023.09.005
  9. Cell. 2023 Sep 26. pii: S0092-8674(23)01032-2. [Epub ahead of print]
    Arginine reprograms metabolism in liver cancer via RBM39.
    Dirk Mossmann, Christoph Müller, Sujin Park, Brendan Ryback, Marco Colombi, Nathalie Ritter, Diana Weißenberger, Eva Dazert, Mairene Coto-Llerena, Sandro Nuciforo, Lauriane Blukacz, Caner Ercan, Veronica Jimenez, Salvatore Piscuoglio, Fatima Bosch, Luigi M Terracciano, Uwe Sauer, Markus H Heim, Michael N Hall.
      Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.
    Keywords:  AGMAT; ARG1; ASNS; RBM39; arginine; hepatocellular carcinoma; indisulam; metabolism
    DOI:  https://doi.org/10.1016/j.cell.2023.09.011
  10. Clin Cancer Res. 2023 Oct 11.
    Nuclear GRP78 Promotes Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma.
    Tiansuo Zhao, Tingting Jiang, Xiaojia Li, Shaofei Chang, Qihui Sun, Fanyang Kong, Xiangyu Kong, Fang Wei, Jie He, Jihui Hao, Keping Xie.
       PURPOSE: Stromal fibrosis limits nutritional supply and disarrays metabolism in pancreatic cancer (PDA). Understanding of the molecular basis underlying metabolic cues would improve PDA management. The current study determined the interaction between glucose-regulated proteins 78 (GRP78) and hypoxia-inducible factor 1a (HIF-1a) and its mechanistic roles underlying PDA response to oxygen and glucose restrains.
    EXPERIMENTAL DESIGN: Gene expression in and its association with clinicopathologic characteristics of PDA patients and mouse models were analyzed using immunohistochemistry. Protein expression and their regulation were measured by Western blot and immunoprecipitation analyses. Protein interactions were determined using gain- and loss-of-function assays and molecular methods, including chromatin immunoprecipitation, co-Immunoprecipitation and dual luciferase reporter.
    RESULTS: There were concomitant overexpression of both GRP78 and HIF-1a in human and mouse PDA tissues and cells. Glucose deprivation increased the expression of GRP78 and HIF-1a, particularly colocalization in nucleus. Induction of HIF-1a expression by glucose deprivation in PDA cells depended on the expression of and its own interaction with GRP78. Mechanistically, increased expression of both HIF-1a and LDHA under glucose deprivation was caused by the direct binding of GRP78 and HIF-1a protein complexes to the promoters of HIF-1a and LDHA genes and transactivation of their transcriptional activity.
    CONCLUSIONS: Protein complex of GRP78 and HIF-1a directly binds to HIF-1a own promoter and LDHA promoter, enhances the transcription of both HIF-1a and LDHA, while glucose deprivation increases GRP78 expression and further enhances HIF-1a and LDHA transcription. Therefore, crosstalk and integration of hypoxia- and hypoglycemia-responsive signaling critically impact PDA metabolic reprogramming and therapeutic resistance.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1143
  11. Hepatol Int. 2023 Oct 12.
    Distinctly altered lipid components in hepatocellular carcinoma relate to impaired T cell-dependent antitumor immunity.
    Xue Cheng, Wei Wang, Ziyao Zhang, Haoquan Zhang, Peng Zhu, Ran He, Mi Wu, Ting Zhou, Ying Jiang, Lang Jiang, Yiqing Chen, Zhihui Liang, Xiongwen Wu, Xiufang Weng.
       BACKGROUND AND AIMS: T cells are master effectors of anti-tumor immunity in cancer. Recent studies suggest that altered lipid metabolism imposed by the tumor microenvironment constrains anti-tumor immunity. However, the tumor-associated lipid species changes that dampen T cell ability to control tumor progression are not fully understood. Here, we plan to clarify the influences of distinctly altered lipid components in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) on T-cell function, aiming to seek lipid metabolic targets for improving T cell anti-tumor effects.
    METHODS: Tumor tissues and non-tumor liver from HCC patients were collected for RNA-sequencing, lipid profiling and T cell characterizing, followed by correlation analysis. Additionally, the effects of significantly changed lipid components on anti-tumor potential of T cells were tested by in vitro cell experiments and/or in vivo tumor inoculated model.
    RESULTS: Altered lipid metabolism coincides with impaired T cell response in HBV-related HCC. Characteristic lipid composition, significantly marked by accumulation of long-chain acylcarnitines (LCACs) and reduction of lysophosphatidylcholines (LPCs), are found in the tumor tissue. Notably, LCACs accumulated are associated with T cells exhaustion and deficient functionality, while LPCs correlate to anti-tumor effects of T cells. In particular, supplement of LPCs, including LPC (20:0) and LPC (22:0), directly promote the activation and IFN-γ secretion of T cells in vitro, and suppress tumor growth in vivo.
    CONCLUSIONS: Our study highlights the distinctly changed lipid components closely related to T cell dysregulation in HCC, and suggests a promising strategy by decreasing LCACs and increasing LPCs for anti-tumor immunotherapy.
    Keywords:  Anti-tumor immunity; Deficient functionality; Hepatocellular carcinoma; IFN-γ secretion; Lipid metabolism; Long-chain acylcarnitines; Lysophosphatidylcholines; T cells exhaustion; Tumor metabolic microenvironment; Tumor-infiltrated T cells
    DOI:  https://doi.org/10.1007/s12072-023-10595-w
  12. Cell Biol Int. 2023 Oct 11.
    Elevated extracellular inorganic phosphate inhibits ecto-phosphatase activity in breast cancer cells: Regulation by hydrogen peroxide.
    Marco A Lacerda-Abreu, José R Meyer-Fernandes.
      For cells to obtain inorganic phosphate, ectoenzymes in the plasma membrane, which contain a catalytic site facing the extracellular environment, hydrolyze phosphorylated molecules. In this study, we show that increased Pi levels in the extracellular environment promote a decrease in ecto-phosphatase activity, which is associated with Pi-induced oxidative stress. High levels of Pi inhibit ecto-phosphatase because Pi generates H2 O2 . Ecto-phosphatase activity is inhibited by H2 O2 , and this inhibition is selective for phospho-tyrosine hydrolysis. Additionally, it is shown that the mechanism of inhibition of ecto-phosphatase activity involves lipid peroxidation. In addition, the inhibition of ecto-phosphatase activity by H2 O2 is irreversible. These findings have new implications for understanding ecto-phosphatase regulation in the tumor microenvironment. H2 O2 stimulated by high Pi inhibits ecto-phosphatase activity to prevent excessive accumulation of extracellular Pi, functioning as a regulatory mechanism of Pi variations in the tumor microenvironment.
    Keywords:  MCF-7; MDA-MB-231; acid phosphatase; ecto-phosphatase activity; inorganic phosphate
    DOI:  https://doi.org/10.1002/cbin.12095
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