bims-mecami 2023-01-01 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–01–01
ten papers selected by
Linda Chan, Cleveland Clinic

Effects of metabolic cancer therapy on tumor microenvironment.
Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.
PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression.
Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer.
Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.
Multi-substrate metabolic tracing reveals marked heterogeneity and dependency on fatty acid metabolism in human prostate cancer.
The role of metabolism on regulatory T cell development and its impact in tumor and transplantation immunity.
Glucose metabolism and tumour microenvironment in pancreatic cancer: A key link in cancer progression.
Interaction between glycolysis‒cholesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer.
Pancreatic stellate cells exploit Wnt/β-catenin/TCF7-mediated glutamine metabolism to promote pancreatic cancer cells growth.

Front Oncol. 2022 ;12 1046630

Effects of metabolic cancer therapy on tumor microenvironment.

Petra Hyroššová, Mirko Milošević, Josef Škoda, Jiří Vachtenheim, Jakub Rohlena, Kateřina Rohlenová.

  Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly - clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.

Keywords:  cancer; endothelial cells; fatty acid metabolism; glycolysis; metabolism; nucleotide metabolism; oxidative phoshorylation; tumor micro environment (TME)

DOI:  https://doi.org/10.3389/fonc.2022.1046630
Cell Metab. 2022 Dec 21. pii: S1550-4131(22)00542-3. [Epub ahead of print]

Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.

Ya-Ting Wang, Alissa J Trzeciak, Waleska Saitz Rojas, Pedro Saavedra, Yan-Ting Chen, Rachel Chirayil, Jon Iker Etchegaray, Christopher D Lucas, Daniel J Puleston, Kayvan R Keshari, Justin S A Perry.

  Apoptotic cell (AC) clearance (efferocytosis) is performed by phagocytes, such as macrophages, that inhabit harsh physiological environments. Here, we find that macrophages display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of ACs. Transcriptional and translational analyses revealed that chronic physiological hypoxia induces two distinct but complimentary states. The first, "primed" state, consists of concomitant transcription and translation of metabolic programs in AC-naive macrophages that persist during efferocytosis. The second, "poised" state, consists of transcription, but not translation, of phagocyte function programs in AC-naive macrophages that are translated during efferocytosis. Mechanistically, macrophages efficiently flux glucose into a noncanonical pentose phosphate pathway (PPP) loop to enhance NADPH production. PPP-derived NADPH directly supports enhanced efferocytosis under physiological hypoxia by ensuring phagolysosomal maturation and redox homeostasis. Thus, macrophages residing under physiological hypoxia adopt states that support cell fitness and ensure performance of essential homeostatic functions rapidly and safely.

Keywords:  apoptotic cell clearance; cellular adaptation; efferocytosis; homeostasis; metabolism; oxygen; pentose phosphate pathway; physiological hypoxia

DOI:  https://doi.org/10.1016/j.cmet.2022.12.005
Nat Commun. 2022 Dec 27. 13(1): 7959

PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression.

Lufei Sui, Suming Wang, Debolina Ganguly, Tyler P El Rayes, Cecilie Askeland, Astrid Børretzen, Danielle Sim, Ole Johan Halvorsen, Gøril Knutsvik, Jarle Arnes, Sura Aziz, Svein Haukaas, William D Foulkes, Diane R Bielenberg, Arturas Ziemys, Vivek Mittal, Rolf A Brekken, Lars A Akslen, Randolph S Watnick.

The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment is the key driver in this process of tumor progression. In order for tumors to progress and metastasize they must reprogram the cells that make up the microenvironment to promote tumor growth and suppress endogenous defense systems, such as the immune and inflammatory response. We have previously demonstrated that stimulation of Tsp-1 in the tumor microenvironment (TME) potently inhibits tumor growth and progression. Here, we identify a novel tumor-mediated mechanism that represses the expression of Tsp-1 in the TME via secretion of the serine protease PRSS2. We demonstrate that PRSS2 represses Tsp-1, not via its enzymatic activity, but by binding to low-density lipoprotein receptor-related protein 1 (LRP1). These findings describe a hitherto undescribed activity for PRSS2 through binding to LRP1 and represent a potential therapeutic strategy to treat cancer by blocking the PRSS2-mediated repression of Tsp-1. Based on the ability of PRSS2 to reprogram the tumor microenvironment, this discovery could lead to the development of therapeutic agents that are indication agnostic.

DOI: https://doi.org/10.1038/s41467-022-35649-9
iScience. 2023 Jan 20. 26(1): 105719

Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer.

Madeline Galbraith, Herbert Levine, José N Onuchic, Dongya Jia.

  Cancer metastasis relies on an orchestration of traits driven by different interacting functional modules, including metabolism and epithelial-mesenchymal transition (EMT). During metastasis, cancer cells can acquire a hybrid metabolic phenotype (W/O) by increasing oxidative phosphorylation without compromising glycolysis and they can acquire a hybrid epithelial/mesenchymal (E/M) phenotype by engaging EMT. Both the W/O and E/M states are associated with high metastatic potentials, and many regulatory links coupling metabolism and EMT have been identified. Here, we investigate the coupled decision-making networks of metabolism and EMT. Their crosstalk can exhibit synergistic or antagonistic effects on the acquisition and stability of different coupled metabolism-EMT states. Strikingly, the aggressive E/M-W/O state can be enabled and stabilized by the crosstalk irrespective of these hybrid states' availability in individual metabolism or EMT modules. Our work emphasizes the mutual activation between metabolism and EMT, providing an important step toward understanding the multifaceted nature of cancer metastasis.

Keywords:  Cancer systems biology; Metabolic flux analysis

DOI:  https://doi.org/10.1016/j.isci.2022.105719
Front Immunol. 2022 ;13 1046755

Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.

Haohao Li, Alison Zhao, Menghua Li, Lizhi Shi, Qiuju Han, Zhaohua Hou.

  Immune checkpoint inhibitors (ICIs) have shown promising therapeutic effects in the treatment of advanced solid cancers, but their overall response rate is still very low for certain tumor subtypes, limiting their clinical scope. Moreover, the high incidence of drug resistance (including primary and acquired) and adverse effects pose significant challenges to the utilization of these therapies in the clinic. ICIs enhance T cell activation and reverse T cell exhaustion, which is a complex and multifactorial process suggesting that the regulatory mechanisms of ICI therapy are highly heterogeneous. Recently, metabolic reprogramming has emerged as a novel means of reversing T-cell exhaustion in the tumor microenvironment; there is increasing evidence that T cell metabolic disruption limits the therapeutic effect of ICIs. This review focuses on the crosstalk between T-cell metabolic reprogramming and ICI therapeutic efficacy, and summarizes recent strategies to improve drug tolerance and enhance anti-tumor effects by targeting T-cell metabolism alongside ICI therapy. The identification of potential targets for altering T-cell metabolism can significantly contribute to the development of methods to predict therapeutic responsiveness in patients receiving ICI therapy, which are currently unknown but would be of great clinical significance.

Keywords:  T cell metabolism; immune checkpoint; immune checkpoints inhibitor; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.1046755
Mol Cancer Res. 2022 Dec 27. pii: MCR-22-0796. [Epub ahead of print]

Multi-substrate metabolic tracing reveals marked heterogeneity and dependency on fatty acid metabolism in human prostate cancer.

Gio Fidelito, David P De Souza, Birunthi Niranjan, William de Nardo, Shivakumar Keerthikumar, Kristin Brown, Renea A Taylor, Matthew J Watt.

Cancer cells undergo metabolic reprogramming to meet increased bioenergetic demands. Studies in cells and mice have highlighted the importance of oxidative metabolism and lipogenesis in prostate cancer, however, the metabolic landscape of human prostate cancer remains unclear. To address this knowledge gap, we performed radiometric (14C) and stable (13C) isotope tracing assays in precision-cut slices of patient-derived xenografts (PDXs). Glucose, glutamine, and fatty acid oxidation was variably upregulated in malignant PDXs compared to benign PDXs. De novo lipogenesis (DNL) and storage of free fatty acids into phospholipids and triacylglycerols were increased in malignant PDXs. There was no difference in substrate utilization between localized and metastatic PDXs and hierarchical clustering revealed marked metabolic heterogeneity across all PDXs. Mechanistically, glucose utilization was mediated by acetyl-CoA production rather than carboxylation of pyruvate, while glutamine entered the TCA cycle through transaminase reactions before being utilized via oxidative or reductive pathways. Blocking fatty acid uptake or fatty acid oxidation with pharmacological inhibitors was sufficient to reduce cell viability in PDX-derived organoids (PDXOs), whereas blockade of DNL, or glucose or glutamine oxidation induced variable and limited therapeutic efficacy. These findings demonstrate that human prostate cancer, irrespective of disease stage, can effectively utilize all metabolic substrates, albeit with marked heterogeneity across tumors. We also confirm that fatty acid uptake and oxidation are targetable metabolic dependencies in human prostate cancer. Implications: Prostate cancer utilizes multiple substrates to fuel energy requirements, yet pharmacological targeting of fatty acid uptake and oxidation reveals metabolic dependencies in localised and metastatic tumors.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0796
Front Immunol. 2022 ;13 1016670

The role of metabolism on regulatory T cell development and its impact in tumor and transplantation immunity.

Aleksey S Bulygin, Julia N Khantakova, Nadezhda S Shkaruba, Hiroshi Shiku, Sergey S Sennikov.

  Regulatory CD4+ T (Treg) cells play a key role in the induction of immune tolerance and in the prevention of autoimmune diseases. Treg cells are defined by the expression of transcription factor FOXP3, which ensures proliferation and induction of the suppressor activity of this cell population. In a tumor microenvironment, after transplantation or during autoimmune diseases, Treg cells can respond to various signals from their environment and this property ensures their suppressor function. Recent studies showed that a metabolic signaling pathway of Treg cells are essential in the control of Treg cell proliferation processes. This review presents the latest research highlights on how the influence of extracellular factors (e.g. nutrients, vitamins and metabolites) as well as intracellular metabolic signaling pathways regulate tissue specificity of Treg cells and heterogeneity of this cell population. Understanding the metabolic regulation of Treg cells should provide new insights into immune homeostasis and disorders along with important therapeutic implications for autoimmune diseases, cancer and other immune-system-mediated disorders.

Keywords:  T cells; fatty acid oxidation; glycolysis; immunometabolism; transplant microenvironment; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.1016670
Front Immunol. 2022 ;13 1038650

Glucose metabolism and tumour microenvironment in pancreatic cancer: A key link in cancer progression.

Shi Dong, Wancheng Li, Xin Li, Zhengfeng Wang, Zhou Chen, Huaqing Shi, Ru He, Chen Chen, Wence Zhou.

  Early and accurate diagnosis and treatment of pancreatic cancer (PC) remain challenging endeavors globally. Late diagnosis lag, high invasiveness, chemical resistance, and poor prognosis are unresolved issues of PC. The concept of metabolic reprogramming is a hallmark of cancer cells. Increasing evidence shows that PC cells alter metabolic processes such as glucose, amino acids, and lipids metabolism and require continuous nutrition for survival, proliferation, and invasion. Glucose metabolism, in particular, regulates the tumour microenvironment (TME). Furthermore, the link between glucose metabolism and TME also plays an important role in the targeted therapy, chemoresistance, radiotherapy ineffectiveness, and immunosuppression of PC. Altered metabolism with the TME has emerged as a key mechanism regulating PC progression. This review shed light on the relationship between TME, glucose metabolism, and various aspects of PC. The findings of this study provide a new direction in the development of PC therapy targeting the metabolism of cancer cells.

Keywords:  glucose metabolism; pancreatic cancer; prognosis; treatment; tumour microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.1038650
Front Immunol. 2022 ;13 979521

Interaction between glycolysis‒cholesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer.

Yan-Jie Chen, Xi Guo, Meng-Ling Liu, Yi-Yi Yu, Yue-Hong Cui, Xi-Zhong Shen, Tian-Shu Liu, Li Liang.

   Background: Metabolic reprogramming is a feature of cancer. However, colon cancer subtypes based on the glycolysis‒cholesterol synthesis axis have not been identified, and little is known about connections between metabolic features and the tumor microenvironment.
Methods: Data for 430 colon cancer cases were extracted from The Cancer Genome Atlas, including transcriptome data, clinical information, and survival outcomes. Glycolysis and cholesterol synthesis-related gene sets were obtained from the Molecular Signatures Database for a gene set variation analysis. The relationship between the genomic landscape and immune landscape were investigated among four metabolic subtypes. Hub genes were determined. The clinical significance of candidate hub gene was evaluated in 264 clinical samples and potential functions were validated in vitro and in vivo.
Results: Colon cancer cases were clustered into four metabolic subtypes: quiescent, glycolytic, cholesterogenic, and mixed. The metabolic subtypes differed with respect to the immune score, stromal score, and estimate score using the ESTIMATE algorithm, cancer-immunity cycle, immunomodulator signatures, and signatures of immunotherapy responses. Patients in the cholesterogenic group had better survival outcomes than those for other subtypes, especially glycolytic. The glycolytic subtype was related to unfavorable clinical characteristics, including high mutation rates in TTN, APC, and TP53, high mutation burden, vascular invasion, right colon cancer, and low-frequency microsatellite instability. GGH, CACNG4, MME, SLC30A2, CKMT2, SYN3, and SLC22A31 were identified as differentially expressed both in glycolytic-cholesterogenic subgroups as well as between colon cancers and healthy samples, and were involved in glycolysis‒cholesterol synthesis. GGH was upregulated in colon cancer; its high expression was correlated with CD4+ T cell infiltration and longer overall survival and it was identified as a favorable independent prognostic factor. The overexpression of GGH in colon cancer-derived cell lines (SW48 and SW480) inhibited PKM, GLUT1, and LDHA expression and decreased the extracellular lactate content and intracellular ATP level. The opposite effects were obtained by GGH silencing. The phenotype associated with GGH was also validated in a xenograft nude mouse model.
Conclusions: Our results provide insight into the connection between metabolism and the tumor microenvironment in colon cancer and provides preliminary evidence for the role of GGH, providing a basis for subsequent studies.

Keywords:  colon cancer (CC); gamma-glutamyl hydrolase (GGH); glycolysis‒cholesterol synthesis axis; metabolic subtypes; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.979521
Cancer Lett. 2022 Dec 21. pii: S0304-3835(22)00527-4. [Epub ahead of print] 216040

Pancreatic stellate cells exploit Wnt/β-catenin/TCF7-mediated glutamine metabolism to promote pancreatic cancer cells growth.

Hangqi Liu, Hui Zhang, Xiaoqian Liu, Wenting Guo, Qiaofei Liu, Longyun Chen, Junyi Pang, Xiaoding Liu, Ruiyu Li, Weimin Tong, Huanwen Wu, Menghua Dai, Zhiyong Liang.

  Pancreatic stellate cells (PSCs) are crucial for metabolism and disease progression in pancreatic ductal adenocarcinoma (PDAC). However, detailed mechanisms of PSCs in glutamine (Gln) metabolism and tumor-stromal metabolic interactions have not been well clarified. Here we showed that tumor tissues displayed Gln deficiency in orthotopic PDAC models. Single-cell RNA sequencing analysis revealed metabolic heterogeneity in PDAC, with significantly higher expression of Gln catabolism pathway in stromal cells. Significantly higher glutamine synthetase (GS) protein expression was further validated in human tissues and cells. Elevated GS levels in tumor and stroma were independently prognostic of poorer prognosis in PDAC patients. Gln secreted by PSCs increased basal oxygen consumption rate in PCCs. Depletion of GS in PSCs significantly decreased PCCs proliferation in vitro and in vivo. Mechanistically, activation of Wnt signaling induced directly binding of β-catenin/TCF7 complex to GS promoter region and upregulated GS expression. Rescue experiments testified that GS overexpression recovered β-catenin knockdown-mediated function on Gln synthesis and tumor-promoting ability of PSCs. Overall, these findings identify Wnt/β-catenin/TCF7/GS-mediated growth-promoting effect of PSCs and provide new insights into stromal Gln metabolism, which may offer novel therapeutic strategies for PDAC.

Keywords:  Cancer-associated fibroblasts; Metabolic crosstalk; Stromal glutamine metabolism; Tumor proliferation; Wnt signaling

DOI:  https://doi.org/10.1016/j.canlet.2022.216040