bims-mecami 2024-05-19 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–05–19
eleven papers selected by
Oltea Sampetrean, Keio University

Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights.
BCKDK Modification Enhances the Anticancer Efficacy of CAR-T Cells by Reprogramming Branched Chain Amino Acid Metabolism.
Immunometabolism in cancer: basic mechanisms and new targeting strategy.
Overcoming Nutrient Stress: Integrin αvβ3-Driven Metabolic Adaptation Supports Tumor Initiation.
Integration of proteomic and metabolomic analysis reveal distinct metabolic alterations of prostate cancer-associated fibroblasts compared to normal fibroblasts from patient's stroma samples.
Hypoxia coordinates the spatial landscape of myeloid cells within glioblastoma to affect survival.
Protocol to detect immune levels, abnormal metabolism, and signaling pathways in tumor tissue based on scRNA-seq obtained from patient databases.
Glycans in melanoma: Drivers of tumour progression but sweet targets to exploit for immunotherapy.
Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.
One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade.
Tumor derived exosomal ENTPD2 impair CD8+ T cell function in colon cancer through ATP-adenosine metabolism reprogramming.

Gastroenterology. 2024 May 15. pii: S0016-5085(24)04917-5. [Epub ahead of print]

Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights.

Sanchita Rauth, Mokenge Malafa, Moorthy P Ponnusamy, Surinder K Batra.

  Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence demonstrated that tumor cell functions are modulated by its microenvironment, compromising fibroblasts, ECMs, microbiome, immune cells, and the enteric nervous system. Along with the TME components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment (TME) and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and cell-extrinsic during tumor progression is critical for developing new therapeutic strategies.

Keywords:  Gastrointestinal cancers; Immune landscapes; Metabolic reprogramming; Targeted therapies; Tumor microenvironment

DOI:  https://doi.org/10.1053/j.gastro.2024.05.005
Mol Ther. 2024 May 10. pii: S1525-0016(24)00319-8. [Epub ahead of print]

BCKDK Modification Enhances the Anticancer Efficacy of CAR-T Cells by Reprogramming Branched Chain Amino Acid Metabolism.

Quanjun Yang, Xinting Zhu, Ping Huang, Chunyan Li, Leng Han, Yonglong Han, Run Gan, Bo Xin, Yixing Tu, Shumin Zhou, Ting Yuan, Juan Hao, Chunqiong Li, Li Zhang, Lei Shi, Cheng Guo.

Altered Branched Chain Amino Acids (BCAA), including leucine, isoleucine and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of Chimeric Antigen Receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and deceasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cells treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and the increasing proportion of CAR-T cells in peripheral circulation. BCKDK-KO CAR-T cells treatment resulted in shorter survival and decreasing percentage of CAR-T cells in peripheral circulation. In conclusion, BCKDK engineered CAR-T cells exert distinct phenotype for the superior anticancer efficiency.

DOI: https://doi.org/10.1016/j.ymthe.2024.05.017
Cell Death Discov. 2024 May 16. 10(1): 236

Immunometabolism in cancer: basic mechanisms and new targeting strategy.

Ranran Su, Yingying Shao, Manru Huang, Donghui Liu, Haiyang Yu, Yuling Qiu.

Maturing immunometabolic research empowers immune regulation novel approaches. Progressive metabolic adaptation of tumor cells permits a thriving tumor microenvironment (TME) in which immune cells always lose the initial killing capacity, which remains an unsolved dilemma even with the development of immune checkpoint therapies. In recent years, many studies on tumor immunometabolism have been reported. The development of immunometabolism may facilitate anti-tumor immunotherapy from the recurrent crosstalk between metabolism and immunity. Here, we discuss clinical studies of the core signaling pathways of immunometabolism and their inhibitors or agonists, as well as the specific functions of these pathways in regulating immunity and metabolism, and discuss some of the identified immunometabolic checkpoints. Understanding the comprehensive advances in immunometabolism helps to revise the status quo of cancer treatment. An overview of the new landscape of immunometabolism. The PI3K pathway promotes anabolism and inhibits catabolism. The LKB1 pathway inhibits anabolism and promotes catabolism. Overactivation of PI3K/AKT/mTOR pathway and IDO, IL4I1, ACAT, Sirt2, and MTHFD2 promote immunosuppression of TME formation, as evidenced by increased Treg and decreased T-cell proliferation. The LKBI-AMPK pathway promotes the differentiation of naive T cells to effector T cells and memory T cells and promotes anti-tumor immunity in DCs.

DOI: https://doi.org/10.1038/s41420-024-02006-2
Cancer Res. 2024 May 15. 84(10): 1543-1545

Overcoming Nutrient Stress: Integrin αvβ3-Driven Metabolic Adaptation Supports Tumor Initiation.

Elena Rainero.

Nutrient stress accompanies several stages of tumor progression, including metastasis formation. Metabolic reprogramming is a hallmark of cancer, and it has been associated with stress tolerance and anchorage-independent cell survival. Adaptive responses are required to support cancer cell survival under these conditions. In this issue of Cancer Research, Nam and colleagues showed that the extracellular matrix (ECM) receptor integrin β3 was upregulated in lung cancer cells in response to nutrient starvation, resulting in increased cell survival that was independent from ECM binding. Delving into the molecular mechanisms responsible for this, the authors found that integrin β3 promoted glutamine metabolism and oxidative phosphorylation (OXPHOS) by activating a Src/AMPK/PGC1α signaling pathway. Importantly, in vivo experiments confirmed that OXPHOS inhibition suppressed tumor initiation in an orthotopic model of lung cancer, while β3 knockout completely abrogated tumor initiation. These observations indicate that targeting signaling pathways downstream of αvβ3 could represent a promising therapeutic avenue to prevent lung cancer progression and metastasis. See related article by Nam et al., p. 1630.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0453
Biochim Biophys Acta Mol Basis Dis. 2024 May 10. pii: S0925-4439(24)00218-7. [Epub ahead of print]1870(6): 167229

Integration of proteomic and metabolomic analysis reveal distinct metabolic alterations of prostate cancer-associated fibroblasts compared to normal fibroblasts from patient's stroma samples.

Guillermo Bordanaba-Florit, Félix Royo, Oihane E Albóniga, Aled Clayton, Juan Manuel Falcón-Pérez, Jason Webber.

  The prostate gland is a complex and heterogeneous organ composed of epithelium and stroma. Whilst many studies into prostate cancer focus on epithelium, the stroma is known to play a key role in disease with the emergence of a cancer-associated fibroblasts (CAF) phenotype associated upon disease progression. In this work, we studied the metabolic rewiring of stromal fibroblasts following differentiation to a cancer-associated, myofibroblast-like, phenotype. We determined that CAFs were metabolically more active compared to normal fibroblasts. This corresponded with a heightened lipogenic metabolism, as both reservoir species and building block compounds. Interestingly, lipid metabolism affects mitochondria functioning yet the mechanisms of lipid-mediated functions are unclear. Data showing oxidised fatty acids and glutathione system are elevated in CAFs, compared to normal fibroblasts, strengthens the hypothesis that increased metabolic activity is related to mitochondrial activity. This manuscript describes mechanisms responsible for the altered metabolic flux and shows that prostate cancer-derived extracellular vesicles can increase basal respiration in normal fibroblasts, mirroring that of the disease-like phenotype. This indicates that extracellular vesicles derived from prostate cancer cells may drive an altered oxygen-dependent metabolism associated to mitochondria in CAFs.

Keywords:  Extracellular vesicles; Human primary fibroblasts; Mass spectrometry; Metabolism; Prostate cancer

DOI:  https://doi.org/10.1016/j.bbadis.2024.167229
Sci Adv. 2024 May 17. 10(20): eadj3301

Hypoxia coordinates the spatial landscape of myeloid cells within glioblastoma to affect survival.

Michael J Haley, Leoma Bere, James Minshull, Sokratia Georgaka, Natalia Garcia-Martin, Gareth Howell, David J Coope, Federico Roncaroli, Andrew King, David C Wedge, Stuart M Allan, Omar N Pathmanaban, David Brough, Kevin N Couper.

Myeloid cells are highly prevalent in glioblastoma (GBM), existing in a spectrum of phenotypic and activation states. We now have limited knowledge of the tumor microenvironment (TME) determinants that influence the localization and the functions of the diverse myeloid cell populations in GBM. Here, we have utilized orthogonal imaging mass cytometry with single-cell and spatial transcriptomic approaches to identify and map the various myeloid populations in the human GBM tumor microenvironment (TME). Our results show that different myeloid populations have distinct and reproducible compartmentalization patterns in the GBM TME that is driven by tissue hypoxia, regional chemokine signaling, and varied homotypic and heterotypic cellular interactions. We subsequently identified specific tumor subregions in GBM, based on composition of identified myeloid cell populations, that were linked to patient survival. Our results provide insight into the spatial organization of myeloid cell subpopulations in GBM, and how this is predictive of clinical outcome.

DOI: https://doi.org/10.1126/sciadv.adj3301
STAR Protoc. 2024 May 14. pii: S2666-1667(24)00230-2. [Epub ahead of print]5(2): 103065

Protocol to detect immune levels, abnormal metabolism, and signaling pathways in tumor tissue based on scRNA-seq obtained from patient databases.

Weiyu Bai.

  Malignant tumor cells are typically more active in terms of metabolism and signal transduction compared to immune and normal cells. Here, we present a protocol to evaluate immune levels, abnormal metabolism, and signaling pathways in tumor tissue based on single-cell sequencing based on patient data obtained from the GEO database. We describe steps for tumor immune microenvironment (TIME)-based evaluation, tumor purity assessment, and identification of abnormal signal transduction and metabolic pathways. We then detail procedures for screening hub genes. For complete details on the use and execution of this protocol, please refer to Bai et al.1.

Keywords:  Bioinformatics; Cancer; Sequence analysis

DOI:  https://doi.org/10.1016/j.xpro.2024.103065
Immunology. 2024 May 14.

Glycans in melanoma: Drivers of tumour progression but sweet targets to exploit for immunotherapy.

Camille Niveau, Eleonora Sosa Cuevas, Philippe Saas, Caroline Aspord.

  Aberrant glycosylation recently emerged as an unmissable hallmark of cancer progression in many cancers. In melanoma, there is growing evidence that the tumour 'glycocode' plays a major role in promoting cell proliferation, invasion, migration, but also dictates the nature of the immune infiltrate, which strongly affects immune cell function, and clinical outcome. Aberrant glycosylation patterns dismantle anti-tumour defence through interactions with lectins on immune cells, which are crucial to shape anti-tumour immunity but also to trigger immune evasion. The glycan/lectin axis represents a new immune subversion pathway that is exploited by melanoma to hijack immune cells and escape from immune control. In this review, we describe the glycosylation features of melanoma tumour cells, and further gather findings related to the role of glycosylation in melanoma tumour progression, deciphering in detail its impact on immunity. We also depict glycan-based strategies aiming at restoring a functional anti-tumour response in melanoma patients. Glycans/lectins emerge as key immune checkpoints with promising translational properties. Exploitation of these pathways could reshape potent anti-tumour immunity while impeding immunosuppressive circuits triggered by aberrant tumour glycosylation patterns, holding great promise for cancer therapy.

Keywords:  glycans; immune subversion; lectins; melanoma; tumour glycocode

DOI:  https://doi.org/10.1111/imm.13801
J Hepatol. 2024 May 15. pii: S0168-8278(24)00342-8. [Epub ahead of print]

Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

Chu-Xu Zhu, Kai Yan, Liang Chen, Rong-Rong Huang, Zhen-Hua Bian, Hao-Ran Wei, Xue-Mei Gu, Yang-Yang Zhao, Meng-Chu Liu, Cai-Xia Suo, Zhi-Kun Li, Zhi-Yi Yang, Min-Qiang Lu, Xue-Feng Hua, Liang Li, Zhi-Bin Zhao, Lin-Chong Sun, Hua-Feng Zhang, Ping Gao, Zhe-Xiong Lian.

   BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme OXCT1. We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear.
METHODS: To investigate the expression pattern of OXCT1 in hepatocellular carcinoma in vivo, we conducted multiplex immunohistochemistry (mIHC) experiments on human HCC specimens. To explore the role of OXCT1 in mouse hepatocellular carcinoma tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice.
RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4 trimethylation (H3K4me3) level in the Arg1 promoter. In addition, Pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreasing CD8+ T-cell exhaustion and deceleration of tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in HCC patients.
CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.
IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping HCC progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for HCC. Here, we found that ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. And the strategic pharmacological intervention or genetic downregulation of OXCT1 in TAMs enhances the antitumor immunity and decelerated tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.

Keywords:  CD8(+) T cell; Hepatocellular carcinoma; Macrophage reprogramming; OXCT1; Pimozide

DOI:  https://doi.org/10.1016/j.jhep.2024.05.007
Cell Chem Biol. 2024 May 16. pii: S2451-9456(24)00169-7. [Epub ahead of print]31(5): 932-943.e8

One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade.

Xincheng Xu, Zihong Chen, Caroline R Bartman, Xi Xing, Kellen Olszewski, Joshua D Rabinowitz.

Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate contributions to purine nucleotides from salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic or lymph node T cells) synthesize purines de novo. Shortage of 1C units for T cell purine synthesis is accordingly a potential bottleneck for anti-tumor immunity. Supplementing 1C units by infusing formate drives formate assimilation into purines in tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling kinetic control of formate production. Safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade in MC38 tumors, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.

DOI: https://doi.org/10.1016/j.chembiol.2024.04.007
Cell Commun Signal. 2024 May 16. 22(1): 274

Tumor derived exosomal ENTPD2 impair CD8+ T cell function in colon cancer through ATP-adenosine metabolism reprogramming.

Mengchen Shi, Linsen Ye, Lu Zhao, Lingyuan He, Junxiong Chen, Jingdan Zhang, Yixi Su, Haiyan Dong, Jiaqi Liu, Liumei Liang, Wenwen Zheng, Yanhong Xiao, Huanliang Liu, Xiangling Yang, Zihuan Yang.

   BACKGROUND: Extracellular ATP-AMP-adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell-derived ATPases in the development and progression of colon cancer.
METHODS: Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8+ T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues.
RESULTS: We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8+ T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8+ T cells.
CONCLUSION: Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP-adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment.

Keywords:  Adenosine; CD8+ T cell; Colon cancer; Ectonucleoside triphosphate diphosphohydrolase; Exosome

DOI:  https://doi.org/10.1186/s12964-024-01654-2