bims-mecami 2023-10-01 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–10–01
thirteen papers selected by
Oltea Sampetrean, Keio University

Editorial: Epigenetic and metabolic regulation of primary and metastatic brain cancers.
Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment.
Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment.
Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities.
Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells.
Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia.
Microenvironmental stiffness induces metabolic reprogramming in glioblastoma.
Metabolic and epigenetic reprogramming in the pathogenesis of glioblastoma: Toward the establishment of "metabolism-based pathology".
Intracellular K + limits T cell exhaustion and preserves antitumor function.
Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.
Tumor metabolic crosstalk and immunotherapy.
Reprogramming the lipid metabolism of dendritic cells in tumor immunomodulation and immunotherapy.
BCAT1 regulates glioblastoma cell plasticity and contributes to immunosuppression.

Front Oncol. 2023 ;13 1271851

Editorial: Epigenetic and metabolic regulation of primary and metastatic brain cancers.

Ryan C Gimple, Briana C Prager, Qi Xie.



Keywords:  brain cancer; brain cancer stem cells; cancer; epigenetics; metabolism; metastasis; primary brain cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2023.1271851
Front Immunol. 2023 ;14 1235812

Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment.

Cristina Viúdez-Pareja, Ewa Kreft, Melissa García-Caballero.

  The tumor microenvironment (TME) is an intricate complex and dynamic structure composed of various cell types, including tumor, stromal and immune cells. Within this complex network, lymphatic endothelial cells (LECs) play a crucial role in regulating immune responses and influencing tumor progression and metastatic dissemination to lymph node and distant organs. Interestingly, LECs possess unique immunomodulatory properties that can either promote or inhibit anti-tumor immune responses. In fact, tumor-associated lymphangiogenesis can facilitate tumor cell dissemination and metastasis supporting immunoevasion, but also, different molecular mechanisms involved in LEC-mediated anti-tumor immunity have been already described. In this context, the crosstalk between cancer cells, LECs and immune cells and how this communication can shape the immune landscape in the TME is gaining increased interest in recent years. In this review, we present a comprehensive and updated report about the immunomodulatory properties of the lymphatic endothelium within the TME, with special focus on primary tumors and tumor-draining lymph nodes. Furthermore, we outline emerging research investigating the potential therapeutic strategies targeting the lymphatic endothelium to enhance anti-tumor immune responses. Understanding the intricate mechanisms involved in LEC-mediated immune modulation in the TME opens up new possibilities for the development of innovative approaches to fight cancer.

Keywords:  immune system; lymphatic endothelial cells; lymphatic vasculature; metastasis; pre-metastatic niche; tumor microenvironment; tumor-draining lymph node

DOI:  https://doi.org/10.3389/fimmu.2023.1235812
Front Oncol. 2023 ;13 1235711

Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment.

Megha Yadav, Blessi N Uikey, Shantnu Singh Rathore, Priyanka Gupta, Diksha Kashyap, Chanchal Kumar, Dhananjay Shukla, Vijayamahantesh, Arvind Singh Chandel, Bharti Ahirwar, Ashish Kumar Singh, Shashi Shekhar Suman, Amit Priyadarshi, Ajay Amit.

  T cells are an important component of adaptive immunity and T-cell-derived lymphomas are very complex due to many functional sub-types and functional elasticity of T-cells. As with other tumors, tissues specific factors are crucial in the development of T-cell lymphomas. In addition to neoplastic cells, T- cell lymphomas consist of a tumor micro-environment composed of normal cells and stroma. Numerous studies established the qualitative and quantitative differences between the tumor microenvironment and normal cell surroundings. Interaction between the various component of the tumor microenvironment is crucial since tumor cells can change the microenvironment and vice versa. In normal T-cell development, T-cells must respond to various stimulants deferentially and during these courses of adaptation. T-cells undergo various metabolic alterations. From the stage of quiescence to attention of fully active form T-cells undergoes various stage in terms of metabolic activity. Predominantly quiescent T-cells have ATP-generating metabolism while during the proliferative stage, their metabolism tilted towards the growth-promoting pathways. In addition to this, a functionally different subset of T-cells requires to activate the different metabolic pathways, and consequently, this regulation of the metabolic pathway control activation and function of T-cells. So, it is obvious that dynamic, and well-regulated metabolic pathways are important for the normal functioning of T-cells and their interaction with the microenvironment. There are various cell signaling mechanisms of metabolism are involved in this regulation and more and more studies have suggested the involvement of additional signaling in the development of the overall metabolic phenotype of T cells. These important signaling mediators include cytokines and hormones. The impact and role of these mediators especially the cytokines on the interplay between T-cell metabolism and the interaction of T-cells with their micro-environments in the context of T-cells lymphomas are discussed in this review article.

Keywords:  T cell lymphoma; cell signaling; cytokine; metabolism; tumor micro environment

DOI:  https://doi.org/10.3389/fonc.2023.1235711
Trends Pharmacol Sci. 2023 Sep 26. pii: S0165-6147(23)00179-7. [Epub ahead of print]

Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities.

Shambhavi Borde, Sandro Matosevic.

  The adaptation of natural killer (NK) cells to conditions in the microenvironment of tumors is deeply affected by their metabolic activity, itself a result of nutrient availability and the metabolism of the cancer cells themselves. Elevated rates of glycolysis and lipid metabolism in cancers not only lead to the accumulation of immunosuppressive byproducts but also contribute to an environment of elevated concentrations of extracellular metabolites. This results in altered NK cell bioenergetics through changes in transcriptional and translational profiles, ultimately affecting their pharmacology and impairing NK cell responses. However, understanding the metabolic processes that drive alterations in immunological signaling on NK cells remains both difficult and vastly underexplored. We discuss the varied and complex drivers of NK cell metabolism in homeostasis and the tumor microenvironment (TME), challenges associated with their targetability, and unexplored therapeutic opportunities.

Keywords:  NK cells; cancer immunotherapy; cancer metabolism; immunometabolism; tumor bioenergetics

DOI:  https://doi.org/10.1016/j.tips.2023.08.009
bioRxiv. 2023 Sep 17. pii: 2023.09.15.557984. [Epub ahead of print]

Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells.

Elliot Ensink, Tessa Jordan, Hyllana C D Medeiros, Galloway Thurston, Anmol Pardal, Lei Yu, Sophia Y Lunt.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality and limited efficacious therapeutic options. PDAC cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. One critical metabolic shift in PDAC cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PK). Pancreatic cancer cells preferentially upregulate pyruvate kinase muscle isoform 2 isoform (PKM2). PKM2 expression reprograms many metabolic pathways, but little is known about its impact on cystine metabolism. Cystine metabolism is critical for supporting survival through its role in defense against ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by unchecked lipid peroxidation. To improve our understanding of the role of PKM2 in cystine metabolism and ferroptosis in PDAC, we generated PKM2 knockout (KO) human PDAC cells. Fascinatingly, PKM2KO cells demonstrate a remarkable resistance to cystine starvation mediated ferroptosis. This resistance to ferroptosis is caused by decreased PK activity, rather than an isoform-specific effect. We further utilized stable isotope tracing to evaluate the impact of glucose and glutamine reprogramming in PKM2KO cells. PKM2KO cells depend on glutamine metabolism to support antioxidant defenses against lipid peroxidation, primarily by increased glutamine flux through the malate aspartate shuttle and utilization of ME1 to produce NADPH. Ferroptosis can be synergistically induced by the combination of PKM2 activation and inhibition of the cystine/glutamate antiporter in vitro . Proof-of-concept in vivo experiments demonstrate the efficacy of this mechanism as a novel treatment strategy for PDAC.
Highlights: PKM2KO in pancreatic ductal adenocarcinoma (PDAC) cells produces enhanced defense against cystine starvation induced ferroptosis.Pharmacologic activation of pyruvate kinase (PK) activity promotes ferroptosis under cystine starvation, while inhibition promotes ferroptosis survival in PDAC cells.Decrease in PK activity reprograms glutamine metabolism to increase use of malic enzyme 1 and promote survival under cystine starvation in PDAC cells. Cystine starvation and activation of pyruvate kinase synergistically decreases progression of pancreatic cancer in vivo .

DOI: https://doi.org/10.1101/2023.09.15.557984
Genes (Basel). 2023 Sep 19. pii: 1818. [Epub ahead of print]14(9):

Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia.

Bryan I Ruiz, Xazmin H Lowman, Ying Yang, Qi Fan, Tianhong Wang, Hongmei Wu, Eric A Hanse, Mei Kong.

  Previous studies have shown that inhibition of TNF family member FN14 (gene: TNFRSF12A) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that TNFRSF12A expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted TNFRSF12A induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the Tnfrsf12a promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of Tnfrsf12a and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model. These findings highlight a connection between metabolic stress and cancer cachexia development.

Keywords:  FN14; TNFRSF12A; alpha-ketoglutarate; cachexia; cancer; colon cancer; histone

DOI:  https://doi.org/10.3390/genes14091818
Cell Rep. 2023 Sep 26. pii: S2211-1247(23)01187-7. [Epub ahead of print]42(10): 113175

Microenvironmental stiffness induces metabolic reprogramming in glioblastoma.

Alireza Sohrabi, Austin E Y T Lefebvre, Mollie J Harrison, Michael C Condro, Talia M Sanazzaro, Gevick Safarians, Itay Solomon, Soniya Bastola, Shadi Kordbacheh, Nadia Toh, Harley I Kornblum, Michelle A Digman, Stephanie K Seidlits.

  The mechanical properties of solid tumors influence tumor cell phenotype and the ability to invade surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state, which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peritumoral brain tissues, but tumor stiffness is heterogeneous where tumor edges are softer than the tumor core. We then developed 3D scaffolds with μ-compressive moduli resembling either stiffer tumor core or softer peritumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis, which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells.

Keywords:  CP: Cancer; CP: Metabolism; extracellular matrix; tissue mechanics

DOI:  https://doi.org/10.1016/j.celrep.2023.113175
Pathol Int. 2023 Sep 27.

Metabolic and epigenetic reprogramming in the pathogenesis of glioblastoma: Toward the establishment of "metabolism-based pathology".

Kenta Masui, Paul S Mischel.

  Molecular genetic approaches are now mandatory for cancer diagnostics, especially for brain tumors. Genotype-based diagnosis has predominated over the phenotype-based approach, with its prognostic and predictive powers. However, comprehensive genetic testing would be difficult to perform in the clinical setting, and translational research is required to histologically decipher the peculiar biology of cancer. Of interest, recent studies have demonstrated discrete links between oncogenotypes and the resultant metabolic phenotypes, revealing cancer metabolism as a promising histologic surrogate to reveal specific characteristics of each cancer type and indicate the best way to manage cancer patients. Here, we provide an overview of our research progress to work on cancer metabolism, with a particular focus on the genomically well-characterized malignant tumor glioblastoma. With the use of clinically relevant animal models and human tissue, we found that metabolic reprogramming plays a major role in the aggressive cancer biology by conferring therapeutic resistance to cancer cells and rewiring their epigenomic landscapes. We further discuss our future endeavor to establish "metabolism-based pathology" on how the basic knowledge of cancer metabolism could be leveraged to improve the management of patients by linking cancer cell genotype, epigenotype, and phenotype through metabolic reprogramming.

Keywords:  cancer metabolism; epigenome; glioblastoma; metabolism-based pathology; molecular genetics

DOI:  https://doi.org/10.1111/pin.13379
bioRxiv. 2023 Sep 15. pii: 2023.09.13.556997. [Epub ahead of print]

Intracellular K + limits T cell exhaustion and preserves antitumor function.

Camille Collier, Kelly Wucherer, Matthew McWhorter, Chelsea Jenkins, Alexandra Bartlett, Rahul Roychoudhuri, Robert Eil.

The cancer-killing activity of T cells is often compromised within tumors, allowing disease progression. We previously found that intratumoral elevations in extracellular K + related to ongoing cell death constrained CD8 + T cell Akt-mTOR signaling and effector function (1,2). To alleviate K + mediated T cell suppression, we pursued genetic means to lower intracellular K + . Transcriptomic analysis of CD8 + T cells demonstrated the Na + /K + ATPase to be robustly and dynamically expressed. CRISPR-Cas9 mediated deletion of the catalytic alpha subunit of the Na + /K + ATPase lowered intracellular K + but produced tonic hyperactivity in multiple signal transduction cascades along with the acquisition of co-inhibitory receptors and terminal differentiation in mouse and human CD8 + T cells. Mechanistically, Na + /K + ATPase disruption led to ROS accumulation due to depletion of intracellular K + in T cells. Antioxidant treatment or high K + media prevented Atp1a1 deficient T cells from exhausted T (T Ex ) cell formation. Consistent with transcriptional and proteomic data suggesting a T Ex cell phenotype, T cells lacking Atp1a1 had compromised persistence and antitumor activity in a syngeneic model of orthotopic murine melanoma. Translational application of these findings will include efforts to lower intracellular K + while limiting ROS accumulation within tumor specific T cells.
Synopsis: High extracellular K + (↑[K + ] e ) is found within tumors and suppresses T cell effector function. Collier et al. find that deletion of the Na + /K + ATPase in T cells lowers intracellular K + and promotes ROS accumulation, tonic signal transduction and T cell exhaustion owing to ROS accumulation. Engineering T cell ion transport is an important consideration for cancer immunotherapy.

DOI: https://doi.org/10.1101/2023.09.13.556997
Commun Biol. 2023 Sep 23. 6(1): 977

Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.

Xinting Zhu, Juan Hao, Hong Zhang, Mengyi Chi, Yaxian Wang, Jinlu Huang, Rong Xu, Zhao Xincai, Bo Xin, Xipeng Sun, Jianping Zhang, Shumin Zhou, Dongdong Cheng, Ting Yuan, Jun Ding, Shuier Zheng, Cheng Guo, Quanjun Yang.

Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.

DOI: https://doi.org/10.1038/s42003-023-05366-0
Clin Transl Oncol. 2023 Sep 23.

Tumor metabolic crosstalk and immunotherapy.

Yiwen Zhang, Yueli Nie, Xiyu Liu, Xitian Wan, Yuanyuan Shi, Keyong Zhang, Pan Wu, Jian He.

  Tumor cells must resist the host's immune system while maintaining growth under harsh conditions of acidity and hypoxia, which indicates that tumors are more robust than normal tissue. Immunotherapeutic agents have little effect on solid tumors, mostly because of the tumor density and the difficulty of penetrating deeply into the tissue to achieve the theoretical therapeutic effect. Various therapeutic strategies targeting the tumor microenvironment (TME) have been developed. Immunometabolic disorders play a dominant role in treatment resistance at both the TME and host levels. Understanding immunometabolic factors and their treatment potential may be a way forward for tumor immunotherapy. Here, we summarize the metabolism of substances that affect tumor progression, the crosstalk between the TME and immunosuppression, and some potential tumor-site targets. We also summarize the progress and challenges of tumor immunotherapy.

Keywords:  Immunotherapy; Metabolic crosstalk; Tumor inflammation; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12094-023-03304-4
Biomed Pharmacother. 2023 Sep 25. pii: S0753-3322(23)01372-0. [Epub ahead of print]167 115574

Reprogramming the lipid metabolism of dendritic cells in tumor immunomodulation and immunotherapy.

Zhanbo Sun, Lingyun Zhang, Lixian Liu.

  Dendritic cells (DCs) are the most potent antigen-presenting cells in the human body. They detect and process environmental signals and communicate with T cells to bridge innate and adaptive immunity. Cell activation, function, and survival are closely associated with cellular metabolism. An increasing number of studies have revealed that lipid metabolism affects DC activation as well as innate and acquired immune responses. Combining lipid metabolic regulation with immunotherapy can strengthen the ability of antigen-presentation and T-cell activation of DCs, improve the existing anti-tumor therapy, and overcome the defects of DC-related therapies in the current stage, which has great potential in cancer therapy. This review summarizes the lipid metabolism of DCs under physiological conditions, analyzes the role of reprogramming the lipid metabolism of DCs in tumor immune regulation, and discusses potential immunotherapeutic strategies.

Keywords:  Dendritic cells; Immunotherapy; Lipid metabolism; Tumor immunomodulation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2023.115574
Neuro Oncol. 2023 Sep 28. pii: noad190. [Epub ahead of print]

BCAT1 regulates glioblastoma cell plasticity and contributes to immunosuppression.

Pavle Boskovic, Nathalie Wilke, Ka-Hou Man, Peter Lichter, Liliana Francois, Bernhard Radlwimmer.

  Glioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Branched-chain amino acid transaminase 1 (BCAT1) is a metabolic enzyme that converts branched-chain amino acids into branched-chain keto acids, depleting cellular α-ketoglutarate and producing glutamate. BCAT1 was shown to drive the growth of glioblastoma and other cancers; however, its oncogenic mechanism remains poorly understood. Here, we show that BCAT1 is crucial for maintaining the poorly differentiated state of glioblastoma cells and that its low expression correlates with a more differentiated glioblastoma phenotype. Furthermore, orthotopic tumor injection into immunocompetent mice demonstrated that the brain microenvironment is sufficient to induce differentiation of Bcat1-KO tumors in vivo. We link the transition to a differentiated cell state to the increased activity of TET demethylases and the hypomethylation and activation of neuronal differentiation genes. In addition, the knockout of Bcat1 attenuated immunosuppression, allowing for an extensive infiltration of CD8 + cytotoxic T-cells and complete abrogation of tumor growth. Further analysis in immunodeficient mice revealed that both tumor cell differentiation and immunomodulation following BCAT1-KO contribute to the long-term suppression of tumor growth. In summary, our study unveils BCAT1's pivotal role in promoting glioblastoma growth by inhibiting tumor cell differentiation and sustaining an immunosuppressive milieu. These findings offer a novel therapeutic avenue for targeting glioblastoma through the inhibition of BCAT1.

Keywords:  BCAT1; differentiation; immunosuppression; neurooncology

DOI:  https://doi.org/10.1093/neuonc/noad190