bims-mecami 2023-10-08 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–10–08
thirteen papers selected by
Oltea Sampetrean, Keio University

Spatially Resolved Metabolomics Combined with the 3D Tumor-Immune Cell Coculture Spheroid Highlights Metabolic Alterations during Antitumor Immune Response.
Editorial: Cancer metabolism: molecular insights, metabolic crosstalk in the tumor microenvironment, and implications for therapy.
The emerging roles of metabolism in the crosstalk between breast cancer cells and tumor-associated macrophages.
Mitochondria Dictate Function and Fate of HSCs and T Cells.
The aging tumor metabolic microenvironment.
Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.
The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism.
The Tumor Microenvironment Promotes Neutrophil Activation in Brain Malignancies.
Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1.
Decreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia.
Irradiated Tumor Cells-Derived Exosomes Modulate Macrophage Polarization by Targeting SHP-2 Mediated Metabolic Reprogramming.
HK3 stimulates immune cell infiltration to promote glioma deterioration.
Calcitriol suppresses gastric cancer progression and cisplatin resistance by inhibiting glycolysis and M2 macrophage polarization through inhibition of mTOR activation.

Anal Chem. 2023 Oct 06.

Spatially Resolved Metabolomics Combined with the 3D Tumor-Immune Cell Coculture Spheroid Highlights Metabolic Alterations during Antitumor Immune Response.

Panpan Chen, Yuhao Han, Lei Wang, Yurong Zheng, Zihan Zhu, Yuan Zhao, Mingqi Zhang, Xiangfeng Chen, Xiao Wang, Chenglong Sun.

The metabolic cross-talk between tumor and immune cells plays key roles in immune cell function and immune checkpoint blockade therapy. However, the characterization of tumor immunometabolism and its spatiotemporal alterations during immune response in a complex tumor microenvironment is challenging. Here, a 3D tumor-immune cell coculture spheroid model was developed to mimic tumor-immune interactions, combined with mass spectrometry imaging-based spatially resolved metabolomics to visualize tumor immunometabolic alterations during immune response. The inhibition of T cells was simulated by coculturing breast tumor spheroids with Jurkat T cells, and the reactivation of T cells can be monitored through diminishing cancer PD-L1 expressions by berberine. This system enables simultaneously screening and imaging discriminatory metabolites that are altered during T cell-mediated antitumor immune response and characterizing the distributions of berberine and its metabolites in tumor spheroids. We discovered that the transport and catabolism of glutamine were significantly reprogrammed during the antitumor immune response at both metabolite and enzyme levels, corresponding to its indispensable roles in energy metabolism and building new biomass. The combination of spatially resolved metabolomics with the 3D tumor-immune cell coculture spheroid visually reveals metabolic interactions between tumor and immune cells and possibly helps decipher the role of immunometabolic alterations in tumor immunotherapy.

DOI: https://doi.org/10.1021/acs.analchem.2c05734
Front Oncol. 2023 ;13 1289397

Editorial: Cancer metabolism: molecular insights, metabolic crosstalk in the tumor microenvironment, and implications for therapy.

Balkrishna Chaube, Parmanand Malvi.



Keywords:  bioenergetics; cancer; cancer/immune metabolism; metabolic disorder and cancer; metabolic imaging; metabolomics; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2023.1289397
Int J Biol Sci. 2023 ;19(15): 4915-4930

The emerging roles of metabolism in the crosstalk between breast cancer cells and tumor-associated macrophages.

Yuxin Liang, Jun He, Xiguang Chen, Liyang Yin, Qiong Yuan, Qiting Zeng, Xuyu Zu, Yingying Shen.

  Breast cancer is the most common cancer affecting women worldwide. Investigating metabolism in breast cancer may accelerate the exploitation of new therapeutic options for immunotherapies. Metabolic reprogramming can confer breast cancer cells (BCCs) with a survival advantage in the tumor microenvironment (TME) and metabolic alterations in breast cancer, and the corresponding metabolic byproducts can affect the function of tumor-associated macrophages (TAMs). Additionally, TAMs undergo metabolic reprogramming in response to signals present in the TME, which can affect their function and breast cancer progression. Here, we review the metabolic crosstalk between BCCs and TAMs in terms of glucose, lipids, amino acids, iron, and adenosine metabolism. Summaries of inhibitors that target metabolism-related processes in BCCs or TAMs within breast cancer have also served as valuable inspiration for novel therapeutic approaches in the fight against this disease. This review provides new perspectives on targeted anticancer therapies for breast cancer that combine immunity with metabolism.

Keywords:  breast cancer; crosstalk; metabolism; targeted therapy; tumor-associated macrophages

DOI:  https://doi.org/10.7150/ijbs.86039
Cancer Immunol Res. 2023 10 04. 11(10): 1303-1313

Mitochondria Dictate Function and Fate of HSCs and T Cells.

Yingxi Xu, Yi-Hsuan Chiang, Ping-Chih Ho, Nicola Vannini.

Hematopoietic stem cells (HSC) and T cells are intimately related, lineage-dependent cell populations that are extensively used as therapeutic products for the treatment of hematologic malignancies and certain types of solid tumors. These cellular therapies can be life-saving treatments; however, their efficacies are often limited by factors influencing their activity and cellular properties. Among these factors is mitochondrial metabolism, which influences the function and fate commitment of both HSCs and T cells. Mitochondria, besides being the "cellular powerhouse," provide metabolic intermediates that are used as substrates for epigenetic modifications and chromatin remodeling, thus, driving cell fate decisions during differentiation. Moreover, mitochondrial fitness and mitochondrial quality control mechanisms are closely related to cellular function, and impairment of these mitochondrial properties associates with cellular dysfunction due to factors such as T-cell exhaustion and aging. Here, we give an overview of the role of mitochondria in shaping the behavior of these lineage-related cell populations. Moreover, we discuss the potential of novel mitochondria-targeting strategies for enhancing HSC- and T cell-based cancer immunotherapies and highlight how design and application of such approaches requires consideration of the metabolic similarities and differences between HSCs and T cells. See related article on p. 1302.

DOI: https://doi.org/10.1158/2326-6066.CIR-22-0685
Curr Opin Biotechnol. 2023 Sep 30. pii: S0958-1669(23)00105-2. [Epub ahead of print]84 102995

The aging tumor metabolic microenvironment.

Steven E Pilley, Edgar Esparza, Peter J Mullen.

Despite the higher incidence of cancer with increasing age, few preclinical or clinical studies incorporate age. This, coupled with an aging world population, requires that we improve our understanding of how aging affects cancer development, progression, and treatment. One key area will be how the tumor microenvironment (TME) changes with age. Metabolite levels are an essential component of the TME, and they are affected by the metabolic requirements of the cells present and systemic metabolite availability. These factors are affected by aging, causing different TME metabolic states between young and older adults. In this review, we will summarize what is known about how aging impacts the TME metabolic state, and suggest how we can improve our understanding of it.

DOI: https://doi.org/10.1016/j.copbio.2023.102995
Res Sq. 2023 Sep 21. pii: rs.3.rs-3356477. [Epub ahead of print]

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.

Geoffrey J Markowitz, Yi Ban, Diamile A Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T Martin, Michael J P Crowley, Tito A Sandoval, Dingcheng Gao, M Laura Martin, Olivier Elemento, Juan R Cubillos-Ruiz, Timothy E McGraw, Nasser K Altorki, Vivek Mittal.

TCF1 high progenitor CD8+ T cells mediate the efficacy of PD-1 blockade, however the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 high central memory-like phenotype and increased responsiveness to PD-1 blockade in vivo . PKM2 KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites, and increased PPP cycling as determined by 1,2 13 C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells towards a TCF1 high population, generated a unique transcriptional landscape, enhanced tumor control in mice in combination with PD-1 blockade, and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state amenable to checkpoint blockade.

DOI: https://doi.org/10.21203/rs.3.rs-3356477/v1
Front Endocrinol (Lausanne). 2023 ;14 1217875

The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism.

Barbara Mensah Sankofi, Estefania Valencia-Rincón, Malika Sekhri, Adriana L Ponton-Almodovar, Jamie J Bernard, Elizabeth A Wellberg.

  Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction. Here, we focus on adipose tissue, highlighting important roles for both adipocytes and fibroblasts in breast cancer progression. One potentially important mediator of adipose tissue effects on breast cancer is the fibroblast growth factor receptor (FGFR) signaling network. Among the many roles of FGFR signaling, we postulate that key mechanisms driving aggressive breast cancer include epithelial-to-mesenchymal transition and cellular metabolic reprogramming. We also pose existing questions that may help better understand breast cancer biology in people with obesity, type 2 diabetes, and poor metabolic health.

Keywords:  adipose; breast cancer; diabetes; fibroblast growth factor; obesity

DOI:  https://doi.org/10.3389/fendo.2023.1217875
Cancer Discov. 2023 Oct 06. OF1

The Tumor Microenvironment Promotes Neutrophil Activation in Brain Malignancies.

Brain tumor-associated neutrophils (TAN) exhibit unique myeloid cell-induced protumor phenotypes.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-159
Cell Metab. 2023 Oct 03. pii: S1550-4131(23)00336-4. [Epub ahead of print]35(10): 1688-1703.e10

Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1.

Yun Zhao, Zhongshun Liu, Guoqiang Liu, Yuting Zhang, Sheng Liu, Dailin Gan, Wennan Chang, Xiaoxia Peng, Eun Suh Sung, Keegan Gilbert, Yini Zhu, Xuechun Wang, Ziyu Zeng, Hope Baldwin, Guanzhu Ren, Jessica Weaver, Anna Huron, Toni Mayberry, Qingfei Wang, Yujue Wang, Maria Elena Diaz-Rubio, Xiaoyang Su, M Sharon Stack, Siyuan Zhang, Xuemin Lu, Ryan D Sheldon, Jun Li, Chi Zhang, Jun Wan, Xin Lu.

  Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.

Keywords:  Acod1; MDSC; breast cancer; ferroptosis; immune checkpoint blockade; immune metabolism; itaconate; metastasis; neutrophil; single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.cmet.2023.09.004
Nat Commun. 2023 Oct 06. 14(1): 6246

Decreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia.

Yasushi Kojima, Emi Mishiro-Sato, Teruaki Fujishita, Kiyotoshi Satoh, Rie Kajino-Sakamoto, Isao Oze, Kazuki Nozawa, Yukiya Narita, Takatsugu Ogata, Keitaro Matsuo, Kei Muro, Makoto Mark Taketo, Tomoyoshi Soga, Masahiro Aoki.

Cancer cachexia is a complex metabolic disorder accounting for ~20% of cancer-related deaths, yet its metabolic landscape remains unexplored. Here, we report a decrease in B vitamin-related liver enzymes as a hallmark of systemic metabolic changes occurring in cancer cachexia. Metabolomics of multiple mouse models highlights cachexia-associated reductions of niacin, vitamin B6, and a glycine-related subset of one-carbon (C1) metabolites in the liver. Integration of proteomics and metabolomics reveals that liver enzymes related to niacin, vitamin B6, and glycine-related C1 enzymes dependent on B vitamins decrease linearly with their associated metabolites, likely reflecting stoichiometric cofactor-enzyme interactions. The decrease of B vitamin-related enzymes is also found to depend on protein abundance and cofactor subtype. These metabolic/proteomic changes and decreased protein malonylation, another cachexia feature identified by protein post-translational modification analysis, are reflected in blood samples from mouse models and gastric cancer patients with cachexia, underscoring the clinical relevance of our findings.

DOI: https://doi.org/10.1038/s41467-023-41952-w
Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)04598-4. [Epub ahead of print]117(2S): S167

Irradiated Tumor Cells-Derived Exosomes Modulate Macrophage Polarization by Targeting SHP-2 Mediated Metabolic Reprogramming.

X Liu, J Yu, D Chen.

PURPOSE/OBJECTIVE(S): Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and support resistance to therapy, constituting promising targets for the development of novel anticancer agents. The efficacy of radiotherapy, a mainstay of cancer treatment, can strongly influence TAMs recruitment and phenotype. Our previous results demonstrated that SHP-2 and PD-L1 inhibition combined with radiotherapy enhances systemic antitumor effects in non-small cell lung cancer (NSCLC). Especially, SHP-2 has an important effect on the polarization of TAM in the context of radiotherapy. However, the immune mechanisms of SHP-2 in TAM remain largely unknown, and this leads us to implement this project.
MATERIALS/METHODS: Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. The bone marrow-derived macrophages (BMDM) and peritoneal macrophages (PM) were derived from C57BL/6 mice for vitro tests. In vivo and in vitro assays were used to identify roles of exosomal miRNA targeting SHP-2. To investigate the regulating function of SHP-2 in TAMs, co-culture experiments, qPCR, Western Blot, Flow Cytometry and Oxygraph-2k were employed. And we also explore tumor growth and tumor environment changes in SHP-2 flox/floxLyz-Cre+/- (CKO) mice.
RESULTS: We found that irradiated tumor cells-derived exosomes reprogramed their energy metabolism and polarized primary macrophages to an anti-inflammatory phenotype. Furthermore, SHP-2 in macrophages was a direct target of exosomal miR-138-5p from irradiated tumor cells. In vitro study also demonstrates that miR-138-5p can down-regulate SHP-2 in the BMDMs and PMs. Further research has shown that SHP-2 negatively regulated glycolysis through dephosphorylating Pyruvate kinase M2 (PKM2) at the Tyr105 site. In addition, SHP-2 can inhabit PKM2 translocation to the nucleus by dephosphorylating PKM2 at the Ser37 site. Thus, the SHP099 (a SHP-2 inhibitor) can uptake and utilization of glucose by SHP-2/PKM2(Tyr105) (Ser37)/β-catenin/LDHA/Glut-1 axis, suggesting that SHP099 plays positive roles on glycolysis and M1-polarized. In vivo study showed that SHP-2 flox/floxLyz-Cre+/- (CKO) mice display enhanced control of solid tumor growth, accompanied by increased the proportion of M1-like macrophages.
CONCLUSION: Our study demonstrates that exosomal miR-138-5p from irradiated tumor cells can modulate macrophage polarization by targeting SHP-2. And SHP-2 negatively regulates glycolysis and polarize macrophage to an M2 phenotype by SHP-2/PKM2(Tyr105) (Ser37)/β-catenin/LDHA/Glut-1 axis.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.267
Cancer Cell Int. 2023 Oct 01. 23(1): 227

HK3 stimulates immune cell infiltration to promote glioma deterioration.

Shupeng Li, Ziwei Li, Xinyu Wang, Junzhe Zhong, Daohan Yu, Hao Chen, Wenbin Ma, Lingling Liu, Minghuang Ye, Ruofei Shen, Chuanlu Jiang, Xiangqi Meng, Jinquan Cai.

   BACKGROUND: Glioma is the most common and lethal type of brain tumor, and it is characterized by unfavorable prognosis and high recurrence rates. The reprogramming of energy metabolism and an immunosuppressive tumor microenvironment (TME) are two hallmarks of tumors. Complex and dynamic interactions between neoplastic cells and the surrounding microenvironment can generate an immunosuppressive TME, which can accelerate the malignant progression of glioma. Therefore, it is crucial to explore associations between energy metabolism and the immunosuppressive TME and to identify new biomarkers for glioma prognosis.
METHODS: In our work, we analyzed the co-expression relationship between glycolytic genes and immune checkpoints based on the transcriptomic data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) and found the correlation between HK3 expression and glioma tumor immune status. To investigate the biological role of HK3 in glioma, we performed bioinformatics analysis and established a mouse glioblastoma (GBM) xenograft model.
RESULTS: Our study showed that HK3 significantly stimulated immune cell infiltration into the glioma TME. Tissue samples with higher HK3 expressive level showed increasing levels of immune cells infiltration, including M2 macrophages, neutrophils, and various subtypes of activated memory CD4+ T cells. Furthermore, HK3 expression was significantly increasing along with the elevated tumor grade, had a higher level in the mesenchymal subtype compared with those in other subtypes of GBM and could independently predict poor outcomes of GBM patients.
CONCLUSION: The present work mainly concentrated on the biological role of HK3 in glioma and offered a novel insight of HK3 regulating the activation of immune cells in the glioma microenvironment. These findings could provide a new theoretical evidence for understanding the metabolic molecular within the glioma microenvironment and identifying new therapeutic targets.

Keywords:  Glioma; Glycolysis; HK3; Immune infiltration; Prognosis

DOI:  https://doi.org/10.1186/s12935-023-03039-w
Environ Toxicol. 2023 Oct 04.

Calcitriol suppresses gastric cancer progression and cisplatin resistance by inhibiting glycolysis and M2 macrophage polarization through inhibition of mTOR activation.

Li Jie, Wang Hengyue, Han Ting.

  The tumor microenvironment (TME) plays a critical role in tumor progression, with macrophages and tumor cells interacting within the TME, influencing cancer development. Despite the known anticancer properties of calcitriol, its role in the TME remains uncertain. This study aimed to explore the effects of calcitriol on macrophages and cancer cells in the TME and its impact on gastric cancer cell proliferation and cisplatin resistance. In vitro TME models were established using conditioned medium from gastric cancer cells (CCM) and macrophages (MCM) treated with or without calcitriol. The results revealed that calcitriol treatment suppressed the expression of glycolysis-related genes and proteins (GLUT1, HKII, LDHA) in MCM-induced gastric cancer cells, leading to increased cancer cell apoptosis and reduced viability, along with decreased Cyclin D1 gene expression. Moreover, calcitriol treatment inhibited mTOR activation in MCM-induced gastric cancer cells. Additionally, calcitriol hindered CCM-induced M2 macrophage polarization by reducing CD206 expression and increasing TNFα gene expression in THP1-derived macrophages, attenuating cisplatin resistance. These findings suggest that calcitriol may impede gastric cancer progression by targeting glycolysis and M2 macrophage polarization through the regulation of mTOR activation in the TME.

Keywords:  M2 macrophage; calcitriol; gastric cancer; glycolysis; mTOR

DOI:  https://doi.org/10.1002/tox.23975