bims-mecami 2024-10-20 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–10–20
nine papers selected by
Oltea Sampetrean, Keio University

Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.
Regulation of CD8+ T cells by lipid metabolism in cancer progression.
The Use of Patient-Derived Organoids in the Study of Molecular Metabolic Adaptation in Breast Cancer.
Hippo pathway in cancer cells induces NCAM1+αSMA+ fibroblasts to modulate tumor microenvironment.
Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.
Beyond Cancer Cells: How the Tumor Microenvironment Drives Cancer Progression.
Metabolic-epigenetic rewiring in CD8+ T cells via lactate-dependent histone lactylation.
Reshaping the tumor microenvironment by degrading glycoimmune checkpoints Siglec-7 and -9.
Pyrimidine metabolism reshapes immune microenvironment and implies poor prognosis in glioma.

Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00103-5. [Epub ahead of print]389 67-103

Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.

Sanjay Pandey, Vandana Anang, Michelle M Schumacher.

  Understanding the intricacies of the metabolic phenotype in immune cells and its plasticity within the tumor microenvironment is pivotal in understanding the pathology and prognosis of cancer. Unfavorable conditions and cellular stress in the tumor microenvironment (TME) exert a profound impact on cellular functions in immune cells, thereby influencing both tumor progression and immune responses. Elevated AMP:ATP ratio, a consequence of limited glucose levels, activate AMP-activated protein kinase (AMPK) while concurrently repressing the activity of mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF-1α). The intricate balance between AMPK, mTOR, and HIF-1α activities defines the metabolic phenotype of immune cells in the TME. These Changes in metabolic phenotype are strongly associated with immune cell functions and play a crucial role in creating a milieu conducive to tumor progression. Insufficiency of nutrient and oxygen supply leads to a metabolic shift in immune cells characterized by a decrease in glycolysis and an increase in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) rates. In most cases, this shift in metabolism is accompanied by a compromise in the effector functions of these immune cells. This metabolic adaptation prompts immune cells to turn down their effector functions, entering a quiescent or immunosuppressive state that may support tumor growth. This article discusses how tumor microenvironment alters the metabolism in immune cells leading to their tolerance and tumor progression, with emphasis on mitochondrial metabolism (OXPHOS and FAO).

Keywords:  AMPK; CAR-T; Fatty acid oxidation; Glycolysis; HIF1α; MTOR; Metabolism; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitochondrial metabolism; OXPHOS; T cell exhaustion; T cell metabolism

DOI:  https://doi.org/10.1016/bs.ircmb.2024.07.003
Cell Mol Immunol. 2024 Oct 14.

Regulation of CD8+ T cells by lipid metabolism in cancer progression.

Yong Tang, Ziqing Chen, Qianying Zuo, Yibin Kang.

  Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.

Keywords:  CD8+T cells; Immunotherapy; Lipid metabolism; Mitochondria; Oxidative phosphorylation

DOI:  https://doi.org/10.1038/s41423-024-01224-z
Int J Mol Sci. 2024 Sep 29. pii: 10503. [Epub ahead of print]25(19):

The Use of Patient-Derived Organoids in the Study of Molecular Metabolic Adaptation in Breast Cancer.

Natalija Glibetic, Scott Bowman, Tia Skaggs, Michael Weichhaus.

  Around 13% of women will likely develop breast cancer during their lifetime. Advances in cancer metabolism research have identified a range of metabolic reprogramming events, such as altered glucose and amino acid uptake, increased reliance on glycolysis, and interactions with the tumor microenvironment (TME), all of which present new opportunities for targeted therapies. However, studying these metabolic networks is challenging in traditional 2D cell cultures, which often fail to replicate the three-dimensional architecture and dynamic interactions of real tumors. To address this, organoid models have emerged as powerful tools. Tumor organoids are 3D cultures, often derived from patient tissue, that more accurately mimic the structural and functional properties of actual tumor tissues in vivo, offering a more realistic model for investigating cancer metabolism. This review explores the unique metabolic adaptations of breast cancer and discusses how organoid models can provide deeper insights into these processes. We evaluate the most advanced tools for studying cancer metabolism in three-dimensional culture models, including optical metabolic imaging (OMI), matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), and recent advances in conventional techniques applied to 3D cultures. Finally, we explore the progress made in identifying and targeting potential therapeutic targets in breast cancer metabolism.

Keywords:  MALDI-MSI; breast cancer; glycolysis; lipid metabolism; metabolism; optical metabolic imaging; organoid; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms251910503
Commun Biol. 2024 Oct 17. 7(1): 1343

Hippo pathway in cancer cells induces NCAM1+αSMA+ fibroblasts to modulate tumor microenvironment.

Chanida Thinyakul, Yasuhisa Sakamoto, Mayuko Shimoda, Yanliang Liu, Suyanee Thongchot, Omnia Reda, Akihiro Nita, Romgase Sakamula, Somponnat Sampattavanich, Ayato Maeda, Paweenapon Chunthaboon, David Nduru, Mayumi Niimura, Yohei Kanamori, Peti Thuwajit, Keiichi I Nakayama, Kun-Liang Guan, Yorifumi Satou, Chanitra Thuwajit, Toshiro Moroishi.

Cancer cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of cancer cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in cancer cells orchestrates the TME by influencing the composition of cancer-associated fibroblasts (CAFs). In a 4T1 mouse breast cancer model, Hippo pathway kinases, large tumor suppressor 1 and 2 (LATS1/2), promoted the formation of neural cell adhesion molecule 1 (NCAM1)+alpha-smooth muscle actin (αSMA)+ CAFs expressing the transforming growth factor-β, which is associated with T cell inactivation and dysfunction. Depletion of LATS1/2 in cancer cells resulted in a less immunosuppressive TME, indicated by the reduced proportions of NCAM1+αSMA+ CAFs and dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1+αSMA+ CAFs were observed in human breast cancer, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy.

DOI: https://doi.org/10.1038/s42003-024-07041-4
EMBO Rep. 2024 Oct 16.

Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.

Amelia M Knudsen-Clark, Daniel Mwangi, Juliana Cazarin, Kristina Morris, Cameron Baker, Lauren M Hablitz, Matthew N McCall, Minsoo Kim, Brian J Altman.

  Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.

Keywords:  Circadian Rhythms; Immuno-oncology; Immunology; Macrophage; Tumor Microenvironment

DOI:  https://doi.org/10.1038/s44319-024-00288-2
Cells. 2024 Oct 09. pii: 1666. [Epub ahead of print]13(19):

Beyond Cancer Cells: How the Tumor Microenvironment Drives Cancer Progression.

Hussein Sabit, Borros Arneth, Shaimaa Abdel-Ghany, Engy F Madyan, Ashraf H Ghaleb, Periasamy Selvaraj, Dong M Shin, Ramireddy Bommireddy, Ahmed Elhashash.

  Liver cancer represents a substantial global health challenge, contributing significantly to worldwide morbidity and mortality. It has long been understood that tumors are not composed solely of cancerous cells, but also include a variety of normal cells within their structure. These tumor-associated normal cells encompass vascular endothelial cells, fibroblasts, and various inflammatory cells, including neutrophils, monocytes, macrophages, mast cells, eosinophils, and lymphocytes. Additionally, tumor cells engage in complex interactions with stromal cells and elements of the extracellular matrix (ECM). Initially, the components of what is now known as the tumor microenvironment (TME) were thought to be passive bystanders in the processes of tumor proliferation and local invasion. However, recent research has significantly advanced our understanding of the TME's active role in tumor growth and metastasis. Tumor progression is now known to be driven by an intricate imbalance of positive and negative regulatory signals, primarily influenced by specific growth factors produced by both inflammatory and neoplastic cells. This review article explores the latest developments and future directions in understanding how the TME modulates liver cancer, with the aim of informing the design of novel therapies that target critical components of the TME.

Keywords:  ECM; TME; immunotherapy; liver cancer; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/cells13191666
Nat Immunol. 2024 Oct 16.

Metabolic-epigenetic rewiring in CD8+ T cells via lactate-dependent histone lactylation.

Renqiang Sun, Hongbo Chi.

DOI: https://doi.org/10.1038/s41590-024-01991-x
bioRxiv. 2024 Oct 12. pii: 2024.10.11.617879. [Epub ahead of print]

Reshaping the tumor microenvironment by degrading glycoimmune checkpoints Siglec-7 and -9.

Chao Wang, Yingqin Hou, Jaroslav Zak, Qinheng Zheng, Kelli A McCord, Mengyao Wu, Ding Zhang, Shereen Chung, Yujie Shi, Jinfeng Ye, Yunlong Zhao, Stephanie Hajjar, Ian A Wilson, James C Paulson, John R Teijaro, Xu Zhou, K Barry Sharpless, Matthew S Macauley, Peng Wu.

Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells. We discovered that T cells express only basal levels of Siglec transcripts; instead, they acquire Siglec-7 and -9 from interacting myeloid cells in the TME via trogocytosis, which impairs their activation and effector function. Mechanistically, Siglec-7 and -9 suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling cascades. Using sulfur fluoride exchange (SuFEx) click chemistry, we developed a ligand that binds to Siglec-7 and -9 with high-affinity and exclusive specificity. Using this ligand, we constructed a Siglec-7/9 degrader that targets membrane Siglec-7 and -9 to the lysosome for degradation. Administration of this degrader induced efficient Siglec degradation in both T cells and myeloid cells in the TME. We found that Siglec-7/9 degradation has a negligible effect on macrophage phagocytosis, but significantly enhances T cell anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, enhanced macrophage antigen presentation, reshaped the TME, and resulted in long-lasting T cell memory and excellent tumor control in multiple murine tumor models. These findings underscore the need to consider exogenous checkpoints acquired by T cells in the TME when selecting specific checkpoint blockade therapy to enhance T cell immunity.

DOI: https://doi.org/10.1101/2024.10.11.617879
Clin Transl Oncol. 2024 Oct 16.

Pyrimidine metabolism reshapes immune microenvironment and implies poor prognosis in glioma.

Ruoyu Huang, Jingchen Yang, Xuejing Li, Huiyuan Chen, Xing Liu.

   BACKGROUND: The metabolic environment of glioma is extremely complex. Pyrimidine metabolism can significantly influence malignant progression of multiple kinds of cancer cells. In this study, we intend to explore the relationship between pyrimidine metabolism and malignant progression of glioma.
METHODS: We analyzed two glioma RNA-sequencing databases to construct a pyrimidine metabolism-related risk signature. An individualized prognosis prediction model based on this risk signature was established. Functional analysis and in vitro experiments were conducted to assess the role of pyrimidine metabolism in the tumor-immune microenvironment and malignant progress of gliomas.
RESULTS: The high-risk group, as predicted by the pyrimidine metabolism-related risk score, showed a tendency toward more malignant entities and poorer survival outcomes. Functional analysis revealed that pyrimidine metabolism significantly regulates the tumor-immune microenvironment. In vitro experiments confirmed that targeting pyrimidine metabolism-related genes can inhibit malignancy of glioma cell.
CONCLUSION: In short, the pyrimidine metabolism-related signature we established could serve as an independent prognostic biomarker in diffuse gliomas and has a close association with regulation of the tumor-immune microenvironment.

Keywords:  Glioma; Prognosis; Pyrimidine metabolism; Risk score; Tumor-immune microenvironment

DOI:  https://doi.org/10.1007/s12094-024-03753-5