bims-mecami 2024-07-21 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–07–21
nine papers selected by
Oltea Sampetrean, Keio University

Metabolic heterogeneity in tumor microenvironment - A novel landmark for immunotherapy.
Targeting tumour metabolism in melanoma to enhance response to immune checkpoint inhibition: A balancing act.
MicroRNA-mediated metabolic regulation of immune cells in cancer: an updated review.
T cell dysfunction and therapeutic intervention in cancer.
Cancer EV stimulate endothelial glycolysis to fuel protein synthesis via mTOR and AMPKα activation.
Asparagine: A key metabolic junction in targeted tumor therapy.
Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells.
Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism.
Imaging Tumor Metabolism.

Autoimmun Rev. 2024 Jul 12. pii: S1568-9972(24)00070-3. [Epub ahead of print] 103579

Metabolic heterogeneity in tumor microenvironment - A novel landmark for immunotherapy.

Chen Chen, Peng Han, Yanping Qing.

  The surrounding non-cancer cells and tumor cells that make up the tumor microenvironment (TME) have various metabolic rhythms. TME metabolic heterogeneity is influenced by the intricate network of metabolic control within and between cells. DNA, protein, transport, and microbial levels are important regulators of TME metabolic homeostasis. The effectiveness of immunotherapy is also closely correlated with alterations in TME metabolism. The response of a tumor patient to immunotherapy is influenced by a variety of variables, including intracellular metabolic reprogramming, metabolic interaction between cells, ecological changes within and between tumors, and general dietary preferences. Although immunotherapy and targeted therapy have made great strides, their use in the accurate identification and treatment of tumors still has several limitations. The function of TME metabolic heterogeneity in tumor immunotherapy is summarized in this article. It focuses on how metabolic heterogeneity develops and is regulated as a tumor progresses, the precise molecular mechanisms and potential clinical significance of imbalances in intracellular metabolic homeostasis and intercellular metabolic coupling and interaction, as well as the benefits and drawbacks of targeted metabolism used in conjunction with immunotherapy. This offers insightful knowledge and important implications for individualized tumor patient diagnosis and treatment plans in the future.

Keywords:  Immunotherapy; Metabolic crosstalk; Metabolic heterogeneity; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.autrev.2024.103579
Cancer Treat Rev. 2024 Jul 11. pii: S0305-7372(24)00130-0. [Epub ahead of print]129 102802

Targeting tumour metabolism in melanoma to enhance response to immune checkpoint inhibition: A balancing act.

J F Tiersma, B Evers, B M Bakker, D J Reijngoud, M de Bruyn, S de Jong, M Jalving.

  Immune checkpoint inhibition has transformed the treatment landscape of advanced melanoma and long-term survival of patients is now possible. However, at least half of the patients do not benefit sufficiently. Metabolic reprogramming is a hallmark of cancer cells and may contribute to both tumour growth and immune evasion by the tumour. Preclinical studies have indeed demonstrated that modulating tumour metabolism can reduce tumour growth while improving the functionality of immune cells. Since metabolic pathways are commonly shared between immune and tumour cells, it is essential to understand how modulating tumour metabolism in patients influences the intricate balance of pro-and anti-tumour immune effects in the tumour microenvironment. The key question is whether modulating tumour metabolism can inhibit tumour cell growth as well as facilitate an anti-tumour immune response. Here, we review current knowledge on the effect of tumour metabolism on the immune response in melanoma. We summarise metabolic pathways in melanoma and non-cancerous cells in the tumour microenvironment and discuss models and techniques available to study the metabolic-immune interaction. Finally, we discuss clinical use of these techniques to improve our understanding of how metabolic interventions can tip the balance towards a favourable, immune permissive microenvironment in melanoma patients.

Keywords:  Immunotherapy; Melanoma; Metabolic-immune interaction; Metabolism

DOI:  https://doi.org/10.1016/j.ctrv.2024.102802
Front Immunol. 2024 ;15 1424909

MicroRNA-mediated metabolic regulation of immune cells in cancer: an updated review.

Sepideh Chowdary Khameneh, Sara Razi, Ramin Lashanizadegan, Sanaz Akbari, Masoud Sayaf, Karimeh Haghani, Salar Bakhtiyari.

  The study of immunometabolism, which examines how immune cells regulate their metabolism to maintain optimal performance, has become an important area of focus in cancer immunology. Recent advancements in this field have highlighted the intricate connection between metabolism and immune cell function, emphasizing the need for further research. MicroRNAs (miRNAs) have gained attention for their ability to post-transcriptionally regulate gene expression and impact various biological processes, including immune function and cancer progression. While the role of miRNAs in immunometabolism is still being explored, recent studies have demonstrated their significant influence on the metabolic activity of immune cells, such as macrophages, T cells, B cells, and dendritic cells, particularly in cancer contexts. Disrupted immune cell metabolism is a hallmark of cancer progression, and miRNAs have been linked to this process. Understanding the precise impact of miRNAs on immune cell metabolism in cancer is essential for the development of immunotherapeutic approaches. Targeting miRNAs may hold potential for creating groundbreaking cancer immunotherapies to reshape the tumor environment and improve treatment outcomes. In summary, the recognition of miRNAs as key regulators of immune cell metabolism across various cancers offers promising potential for refining cancer immunotherapies. Further investigation into how miRNAs affect immune cell metabolism could identify novel therapeutic targets and lead to the development of innovative cancer immunotherapies.

Keywords:  cancer; immune cells; immunotherapy; metabolic regulation; microRNAs (miRNAs)

DOI:  https://doi.org/10.3389/fimmu.2024.1424909
Nat Immunol. 2024 Jul 18.

T cell dysfunction and therapeutic intervention in cancer.

Caitlin C Zebley, Dietmar Zehn, Stephen Gottshalk, Hongbo Chi.

Recent advances in immunotherapy have affirmed the curative potential of T cell-based approaches for treating relapsed and refractory cancers. However, the therapeutic efficacy is limited in part owing to the ability of cancers to evade immunosurveillance and adapt to immunological pressure. In this Review, we provide a brief overview of cancer-mediated immunosuppressive mechanisms with a specific focus on the repression of the surveillance and effector function of T cells. We discuss CD8+ T cell exhaustion and functional heterogeneity and describe strategies for targeting the molecular checkpoints that restrict T cell differentiation and effector function to bolster immunotherapeutic effects. We also delineate the emerging contributions of the tumor microenvironment to T cell metabolism and conclude by highlighting discovery-based approaches for developing future cellular therapies. Continued exploration of T cell biology and engineering hold great promise for advancing therapeutic interventions for cancer.

DOI: https://doi.org/10.1038/s41590-024-01896-9
J Extracell Vesicles. 2024 Jul;13(7): e12449

Cancer EV stimulate endothelial glycolysis to fuel protein synthesis via mTOR and AMPKα activation.

Joël E J Beaumont, Lydie M O Barbeau, Jinzhe Ju, Kim G Savelkouls, Freek G Bouwman, Marijke I Zonneveld, Annelies Bronckaers, Kim R Kampen, Tom G H Keulers, Kasper M A Rouschop.

  Hypoxia is a common feature of solid tumours and activates adaptation mechanisms in cancer cells that induce therapy resistance and has profound effects on cellular metabolism. As such, hypoxia is an important contributor to cancer progression and is associated with a poor prognosis. Metabolic alterations in cells within the tumour microenvironment support tumour growth via, amongst others, the suppression of immune reactions and the induction of angiogenesis. Recently, extracellular vesicles (EV) have emerged as important mediators of intercellular communication in support of cancer progression. Previously, we demonstrated the pro-angiogenic properties of hypoxic cancer cell derived EV. In this study, we investigate how (hypoxic) cancer cell derived EV mediate their effects. We demonstrate that cancer derived EV regulate cellular metabolism and protein synthesis in acceptor cells through increased activation of mTOR and AMPKα. Using metabolic tracer experiments, we demonstrate that EV stimulate glucose uptake in endothelial cells to fuel amino acid synthesis and stimulate amino acid uptake to increase protein synthesis. Despite alterations in cargo, we show that the effect of cancer derived EV on recipient cells is primarily determined by the EV producing cancer cell type rather than its oxygenation status.

Keywords:  angiogenesis; extracellular vesicles; hypoxia; metabolism

DOI:  https://doi.org/10.1002/jev2.12449
Pharmacol Res. 2024 Jul 14. pii: S1043-6618(24)00237-8. [Epub ahead of print]206 107292

Asparagine: A key metabolic junction in targeted tumor therapy.

Xuan Wang, Weijian Gong, Xueyou Xiong, Xuemei Jia, Juan Xu.

  Nutrient bioavailability in the tumor microenvironment plays a pivotal role in tumor proliferation and metastasis. Among these nutrients, glutamine is a key substance that promotes tumor growth and proliferation, and its downstream metabolite asparagine is also crucial in tumors. Studies have shown that when glutamine is exhausted, tumor cells can rely on asparagine to sustain their growth. Given the reliance of tumor cell proliferation on asparagine, restricting its bioavailability has emerged as promising strategy in cancer treatment. For instance, the use of asparaginase, an enzyme that depletes asparagine, has been one of the key chemotherapies for acute lymphoblastic leukemia (ALL). However, tumor cells can adapt to asparagine restriction, leading to reduced chemotherapy efficacy, and the mechanisms by which different genetically altered tumors are sensitized or adapted to asparagine restriction vary. We review the sources of asparagine and explore how limiting its bioavailability impacts the progression of specific genetically altered tumors. It is hoped that by targeting the signaling pathways involved in tumor adaptation to asparagine restriction and certain factors within these pathways, the issue of drug resistance can be addressed. Importantly, these strategies offer precise therapeutic approaches for genetically altered cancers.

Keywords:  Asparaginase (Pubchem CID: 436058); Asparagine; Asparagine synthetase (Pubchem CID: 381121140); Aspartic acid (Pubchem CID: 5960); Cancer; Genetic Alteration; Glutamic acid (Pubchem CID: 33032); Glutaminase (Pubchem CID: 72950407); Glutamine (Pubchem CID: 5961); Histidine (Pubchem CID: 6274); L-asparagine (Pubchem CID: 6267); Metabolism; Serine (Pubchem CID: 5951); Targeted therapy; Threonine (Pubchem CID: 6288)

DOI:  https://doi.org/10.1016/j.phrs.2024.107292
Cell Oncol (Dordr). 2024 Jul 18.

Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells.

Silvia Peppicelli, Lido Calorini, Francesca Bianchini, Laura Papucci, Lucia Magnelli, Elena Andreucci.

  The complex and continuously evolving features of the tumor microenvironment, varying between tumor histotypes, are characterized by the presence of host cells and tumor cells embedded in a milieu shaped by hypoxia and low pH, resulting from the frequent imbalance between vascularity and tumor cell proliferation. These microenvironmental metabolic stressors play a crucial role in remodeling host cells and tumor cells, contributing to the stimulation of cancer cell heterogeneity, clonal evolution, and multidrug resistance, ultimately leading to progression and metastasis. The extracellular vesicles (EVs), membrane-enclosed structures released into the extracellular milieu by tumor/host cells, are now recognized as critical drivers in the complex intercellular communication between tumor cells and the local cellular components in a hypoxic/acidic microenvironment. Understanding the intricate molecular mechanisms governing the interactions between tumor and host cells within a hypoxic and acidic microenvironment, triggered by the release of EVs, could pave the way for innovative strategies to disrupt the complex interplay of cancer cells with their microenvironment. This approach may contribute to the development of an efficient and safe therapeutic strategy to combat cancer progression. Therefore, we review the major findings on the release of EVs in a hypoxic/acidic tumor microenvironment to appreciate their role in tumor progression toward metastatic disease.

Keywords:  Acidosis; Cancer progression; Extracellular vesicles; Hypoxia; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13402-024-00969-z
bioRxiv. 2024 Jul 11. pii: 2024.07.08.602554. [Epub ahead of print]

Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism.

KayLee K Steiner, Arissa C Young, Andrew R Patterson, Erin Q Jennings, Channing Chi, Zaid Hatem, Darren Heintzman, Ayaka Sugiura, Emily N Arner, Allison E Sewell, Matthew Z Madden, Richmond Okparaugo, Emilia V Fallman, Katherine Gibson-Corley, Kelsey Voss, Denis Mogilenko, Jeffrey Rathmell.

Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid-associated genes essential for T cell subset functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as highly impactful. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Effector and memory T cells were reduced in Mecrfl/fl; Cd4cre mice, and MECR was required for activated CD4+ T cells to efficiently proliferate, differentiate, and survive. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to cell death and sensitivity to ferroptosis. Importantly, Mecr-deficient T cells exhibited fitness disadvantages in inflammatory, tumor, and infection models. mtFAS and MECR thus play important roles in activated T cells and may provide targets to modulate immune functions in inflammatory diseases. The immunological state of MECR- and mtFAS-deficient patients may also be compromised.

DOI: https://doi.org/10.1101/2024.07.08.602554
Cold Spring Harb Perspect Med. 2024 Jul 15. pii: a041551. [Epub ahead of print]

Imaging Tumor Metabolism.

Thomas Ruan, Kayvan R Keshari.

Molecular imaging-the mapping of molecular and cellular processes in vivo-has the unique capability to interrogate cancer metabolism in its spatial contexts. This work describes the usage of the two most developed modalities for imaging metabolism in vivo: positron emission tomography (PET) and magnetic resonance (MR). These techniques can be used to probe glycolysis, glutamine metabolism, anabolic metabolism, redox state, hypoxia, and extracellular acidification. This review aims to provide an overview of the strengths and limitations of currently available molecular imaging strategies.

DOI: https://doi.org/10.1101/cshperspect.a041551