bims-mecami 2023-04-02 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–04–02
eleven papers selected by
Oltea Sampetrean, Keio University

A metabolic vulnerability of pancreatic cancer.
Metabolic codependencies in the tumor microenvironment and gastric cancer: Difficulties and opportunities.
Fatty acid metabolism and radiation-induced anti-tumor immunity.
The role of metabolic reprogramming of tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment.
Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes.
Integrating bulk and single-cell RNA sequencing data reveals the relationship between intratumor microbiome signature and host metabolic heterogeneity in breast cancer.
An immunometabolism subtyping system identifies S100A9+ macrophage as an immune therapeutic target in colorectal cancer based on multiomics analysis.
Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer.
Glutamine metabolism-related genes predict prognosis and reshape tumor microenvironment immune characteristics in diffuse gliomas.
Dietary Folate Deficiency Promotes Lactate Metabolic Disorders to Sensitize Lung Cancer Metastasis through MTOR-Signaling-Mediated Druggable Oncotargets.
Editorial: Targeting glucose metabolism in cancer immunity and immunotherapy.

Nature. 2023 Mar 29.

A metabolic vulnerability of pancreatic cancer.

Daniel J Puleston.



Keywords:  Cancer; Medical research

DOI:  https://doi.org/10.1038/d41586-023-00848-x
Biomed Pharmacother. 2023 Mar 27. pii: S0753-3322(23)00389-X. [Epub ahead of print]162 114601

Metabolic codependencies in the tumor microenvironment and gastric cancer: Difficulties and opportunities.

Xihe Zhao, Kai Li, Mengyu Chen, Lei Liu.

  Oncogenesis and the development of tumors affect metabolism throughout the body. Metabolic reprogramming (also known as metabolic remodeling) is a feature of malignant tumors that is driven by oncogenic changes in the cancer cells themselves as well as by cytokines in the tumor microenvironment. These include endothelial cells, matrix fibroblasts, immune cells, and malignant tumor cells. The heterogeneity of mutant clones is affected by the actions of other cells in the tumor and by metabolites and cytokines in the microenvironment. Metabolism can also influence immune cell phenotype and function. Metabolic reprogramming of cancer cells is the result of a convergence of both internal and external signals. The basal metabolic state is maintained by internal signaling, while external signaling fine-tunes the metabolic process based on metabolite availability and cellular needs. This paper reviews the metabolic characteristics of gastric cancer, focusing on the intrinsic and extrinsic mechanisms that drive cancer metabolism in the tumor microenvironment, and interactions between tumor cell metabolic changes and microenvironment metabolic changes. This information will be helpful for the individualized metabolic treatment of gastric cancers.

Keywords:  Codependencies; Gastric cancer; Immunal reprogramming; Metabolism; Microenviroment

DOI:  https://doi.org/10.1016/j.biopha.2023.114601
Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(23)00003-5. [Epub ahead of print]376 121-141

Fatty acid metabolism and radiation-induced anti-tumor immunity.

Mara De Martino, Camille Daviaud, Edgar Hajjar, Claire Vanpouille-Box.

  Fatty acid metabolic reprogramming has emerged as a major regulator of anti-tumor immune responses with large body of evidence that demonstrate its ability to impact the differentiation and function of immune cells. Therefore, depending on the metabolic cues that stem in the tumor microenvironment, the tumor fatty acid metabolism can tilt the balance of inflammatory signals to either promote or impair anti-tumor immune responses. Oxidative stressors such as reactive oxygen species generated from radiation therapy can rewire the tumor energy supply, suggesting that radiation therapy can further perturb the energy metabolism of a tumor by promoting fatty acid production. In this review, we critically discuss the network of fatty acid metabolism and how it regulates immune response especially in the context of radiation therapy.

Keywords:  Fatty acid metabolism; Immunostimulation; Immunosuppression; Nucleic acid sensing; Radiation therapy; Radioresistance

DOI:  https://doi.org/10.1016/bs.ircmb.2023.01.003
Biomed Pharmacother. 2023 May;pii: S0753-3322(23)00292-5. [Epub ahead of print]161 114504

The role of metabolic reprogramming of tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment.

Lunxu Li, Yu Tian.

  Macrophages are potent immune effector cells in innate immunity and exert dual-effects in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) make up a significant portion of TME immune cells. Similar to M1/M2 macrophages, TAMs are also highly plastic, and their functions are regulated by cytokines, chemokines and other factors in the TME. The metabolic changes in TAMs are significantly associated with polarization towards a protumour or antitumour phenotype. The metabolites generated via TAM metabolic reprogramming in turn promote tumor progression and immune tolerance. In this review, we explore the metabolic reprogramming of TAMs in terms of energy, amino acid and fatty acid metabolism and the potential roles of these changes in immune suppression.

Keywords:  Immunosuppression; Metabolism; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.biopha.2023.114504
Front Immunol. 2023 ;14 1121565

Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes.

Priyanka Maridhi Nanjireddy, Scott H Olejniczak, Nataliya Prokopenko Buxbaum.

  Genetically engineered chimeric antigen receptor (CAR) T cells can cure patients with cancers that are refractory to standard therapeutic approaches. To date, adoptive cell therapies have been less effective against solid tumors, largely due to impaired homing and function of immune cells within the immunosuppressive tumor microenvironment (TME). Cellular metabolism plays a key role in T cell function and survival and is amenable to manipulation. This manuscript provides an overview of known aspects of CAR T metabolism and describes potential approaches to manipulate metabolic features of CAR T to yield better anti-tumor responses. Distinct T cell phenotypes that are linked to cellular metabolism profiles are associated with improved anti-tumor responses. Several steps within the CAR T manufacture process are amenable to interventions that can generate and maintain favorable intracellular metabolism phenotypes. For example, co-stimulatory signaling is executed through metabolic rewiring. Use of metabolic regulators during CAR T expansion or systemically in the patient following adoptive transfer are described as potential approaches to generate and maintain metabolic states that can confer improved in vivo T cell function and persistence. Cytokine and nutrient selection during the expansion process can be tailored to yield CAR T products with more favorable metabolic features. In summary, improved understanding of CAR T cellular metabolism and its manipulations have the potential to guide the development of more effective adoptive cell therapies.

Keywords:  CAR T cell; adoptive cell therapy (ACT); cell metabolism; immunometabolism; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1121565
Front Immunol. 2023 ;14 1140995

Integrating bulk and single-cell RNA sequencing data reveals the relationship between intratumor microbiome signature and host metabolic heterogeneity in breast cancer.

Fangyue Chen, Jun Yang, Youxiang Guo, Dongwei Su, Yuan Sheng, Yanmei Wu.

   Introduction: Nowadays, it has been recognized that gut microbiome can indirectly modulate cancer susceptibility or progression. However, whether intratumor microbes are parasitic, symbiotic, or merely bystanders in breast cancer is not fully understood. Microbial metabolite plays a pivotal role in the interaction of host and microbe via regulating mitochondrial and other metabolic pathways. And the relationship between tumor-resident microbiota and cancer metabolism remains an open question.
Methods: 1085 breast cancer patients with normalized intratumor microbial abundance data and 32 single-cell RNA sequencing samples were retrieved from public datasets. We used the gene set variation analysis to evaluate the various metabolic activities of breast cancer samples. Furthermore, we applied Scissor method to identify microbe-associated cell subpopulations from single-cell data. Then, we conducted comprehensive bioinformatic analyses to explore the association between host and microbe in breast cancer.
Results: Here, we found that the metabolic status of breast cancer cells was highly plastic, and some microbial genera were significantly correlated with cancer metabolic activity. We identified two distinct clusters based on microbial abundance and tumor metabolism data. And dysregulation of the metabolic pathway was observed among different cell types. Metabolism-related microbial scores were calculated to predict overall survival in patients with breast cancer. Furthermore, the microbial abundance of the specific genus was associated with gene mutation due to possible microbe-mediated mutagenesis. The infiltrating immune cell compositions, including regulatory T cells and activated NK cells, were significantly associated with the metabolism-related intratumor microbes, as indicated in the Mantel test analysis. Moreover, the mammary metabolism-related microbes were related to T cell exclusion and response to immunotherapy.
Conclusions: Overall, the exploratory study shed light on the potential role of the metabolism-related microbiome in breast cancer patients. And the novel treatment will be realized by further investigating the metabolic disturbance in host and intratumor microbial cells.

Keywords:  breast cancer; immune cell; intratumoral microbiome; metabolic heterogeneity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1140995
Cell Rep Med. 2023 Mar 24. pii: S2666-3791(23)00093-9. [Epub ahead of print] 100987

An immunometabolism subtyping system identifies S100A9+ macrophage as an immune therapeutic target in colorectal cancer based on multiomics analysis.

Xuanwen Bao, Danyang Wang, Xiaomeng Dai, Chuan Liu, Hangyu Zhang, Yuzhi Jin, Zhou Tong, Bin Li, Chuchu Tong, Shan Xin, Xin Li, Yanfang Wang, Lulu Liu, Xudong Zhu, Qihan Fu, Yi Zheng, Jingwen Deng, Weihong Tian, Tiannan Guo, Peng Zhao, Wenbin Cheng, Weijia Fang.

  Immunometabolism in the tumor microenvironment (TME) and its influence on the immunotherapy response remain uncertain in colorectal cancer (CRC). We perform immunometabolism subtyping (IMS) on CRC patients in the training and validation cohorts. Three IMS subtypes of CRC, namely, C1, C2, and C3, are identified with distinct immune phenotypes and metabolic properties. The C3 subtype exhibits the poorest prognosis in both the training cohort and the in-house validation cohort. The single-cell transcriptome reveals that a S100A9+ macrophage population contributes to the immunosuppressive TME in C3. The dysfunctional immunotherapy response in the C3 subtype can be reversed by combination treatment with PD-1 blockade and an S100A9 inhibitor tasquinimod. Taken together, we develop an IMS system and identify an immune tolerant C3 subtype that exhibits the poorest prognosis. A multiomics-guided combination strategy by PD-1 blockade and tasquinimod improves responses to immunotherapy by depleting S100A9+ macrophages in vivo.

Keywords:  CRC; IMS; S100A9(+) macrophage; TME; colorectal cancer; immunometabolism subtyping; immunotherapy; multiomics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2023.100987
Nature. 2023 Mar 29.

Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer.

Min-Sik Lee, Courtney Dennis, Insia Naqvi, Lucas Dailey, Alireza Lorzadeh, George Ye, Tamara Zaytouni, Ashley Adler, Daniel S Hitchcock, Lin Lin, Megan T Hoffman, Aladdin M Bhuiyan, Jaimie L Barth, Miranda E Machacek, Mari Mino-Kenudson, Stephanie K Dougan, Unmesh Jadhav, Clary B Clish, Nada Y Kalaany.

There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence1 and poor prognosis2. Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy3,4. Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis5,6. This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.

DOI: https://doi.org/10.1038/s41586-023-05891-2
Front Neurol. 2023 ;14 1104738

Glutamine metabolism-related genes predict prognosis and reshape tumor microenvironment immune characteristics in diffuse gliomas.

Huanhuan Fan, Shuxin Zhang, Yunbo Yuan, Siliang Chen, Wenhao Li, Zhihao Wang, Yufan Xiang, Junhong Li, Xiaohong Ma, Yanhui Liu.

   Background: Diffuse gliomas possess a kind of malignant brain tumor with high mortality. Glutamine represents the most abundant and versatile amino acid in the body. Glutamine not only plays an important role in cell metabolism but also involves in cell survival and malignancies progression. Recent studies indicate that glutamine could also affect the metabolism of immune cells in the tumor microenvironment (TME).
Materials and methods: The transcriptome data and clinicopathological information of patients with glioma were acquired from TCGA, CGGA, and West China Hospital (WCH). The glutamine metabolism-related genes (GMRGs) were retrieved from the Molecular Signature Database. Consensus clustering analysis was used to discover expression patterns of GMRGs, and glutamine metabolism risk scores (GMRSs) were established to model tumor aggressiveness-related GMRG expression signature. ESTIMATE and CIBERSORTx were applied to depict the TME immune landscape. The tumor immunological phenotype analysis and TIDE were utilized for predicting the therapeutic response of immunotherapy.
Results: A total of 106 GMRGs were retrieved. Two distinct clusters were established by consensus clustering analysis, which showed a close association with the IDH mutational status of gliomas. In both IDH-mutant and IDH-wildtype gliomas, cluster 2 had significantly shorter overall survival compared with cluster 1, and the differentially expressed genes between the two clusters enriched in pathways related to malignant transformation as well as immunity. In silico TME analysis of the two IDH subtypes revealed not only significantly different immune cell infiltrations and immune phenotypes between the GMRG expression clusters but also different predicted responses to immunotherapy. After the screening, a total of 10 GMRGs were selected to build the GMRS. Survival analysis demonstrated the independent prognostic role of GMRS. Prognostic nomograms were established to predict 1-, 2-, and 3-year survival rates in the four cohorts.
Conclusion: Different subtypes of glutamine metabolism could affect the aggressiveness and TME immune features of diffuse glioma, despite their IDH mutational status. The expression signature of GMRGs could not only predict the outcome of patients with glioma but also be combined into an accurate prognostic nomogram.

Keywords:  diffuse glioma; glutamine metabolism; immune; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fneur.2023.1104738
Nutrients. 2023 Mar 21. pii: 1514. [Epub ahead of print]15(6):

Dietary Folate Deficiency Promotes Lactate Metabolic Disorders to Sensitize Lung Cancer Metastasis through MTOR-Signaling-Mediated Druggable Oncotargets.

Wan-Jing Chen, Su-Yu Huang, Yi-Wen Chen, Yi-Fang Liu, Rwei-Fen S Huang.

  Lactate metabolism plays a pivotal role in cancers but is often overlooked in lung cancer (LC). Folate deficiency has been linked to lung cancer development, but its impact on lactate metabolism and cancer malignancy is unclear. To investigate this, mice were fed either a folate-deficient (FD) or control diet and intrapleurally implanted with lung cancer cells pre-exposed to FD growth medium. Results showed that FD promoted lactate over-production and the formation of tumor oncospheroids (LCSs) with increased metastatic, migration, and invasion potential. Mice implanted with these cells and fed an FD diet developed hyperlactatemia in blood and lungs. This coincided with increased expression of hexokinase 2 (HK2), lactate dehydrogenase (LDH), and decreased expression of pyruvate dehydrogenase (PDH). Pre-treatment of the FD-LCS-implanted mice with the mTORC1 inhibitor, rapamycin, and the anti-metabolic drug metformin abolished FD/LCS-activated mTORC1 and its targets including HIF1α, HK2, LDH, and monocarboxylate transporters (MCT1 and MCT4), which coincided with the reduction in lactate disorders and prevention of LC metastasis. The findings suggest that dietary FD promotes lactate metabolic disorders that sensitize lung cancer metastasis through mTOR-signaling-mediated targets.

Keywords:  dietary folate deficiency; lactate metabolic disorders; lung cancer; mTORC1 signaling; metastasis; oncotargets

DOI:  https://doi.org/10.3390/nu15061514
Front Immunol. 2023 ;14 1171274

Editorial: Targeting glucose metabolism in cancer immunity and immunotherapy.

Olivier Feron, Chih-Hao Chang, Frédérique Végran.



Keywords:  GLUT3; fluorodeoxyglucose; gamma-glutamyl hydrolase; glucose transporter; glycolysis; immunometabolism; pancreatic cancer

DOI:  https://doi.org/10.3389/fimmu.2023.1171274