bims-mecami 2024-06-16 papers

Issue of 2024–06–16
seven papers selected by
Oltea Sampetrean, Keio University

Cold Spring Harb Perspect Med. 2024 Jun 10. pii: a041544. [Epub ahead of print]

Laura V Pinheiro, Pedro Costa-Pinheiro, Kathryn E Wellen.

Metabolic reprogramming in cancer allows cells to survive in harsh environments and sustain macromolecular biosynthesis to support proliferation. In addition, metabolites play crucial roles as signaling molecules. Metabolite fluctuations are detected by various sensors in the cell to regulate gene expression, metabolism, and signal transduction. Metabolic signaling mechanisms contribute to tumorigenesis by altering the physiology of cancer cells themselves, as well as that of neighboring cells in the tumor microenvironment. In this review, we discuss principles of metabolic signaling and provide examples of how cancer cells take advantage of metabolic signals to promote cell proliferation and evade the immune system, thereby contributing to tumor growth and progression.

DOI: https://doi.org/10.1101/cshperspect.a041544

Trends Immunol. 2024 Jun 13. pii: S1471-4906(24)00120-0. [Epub ahead of print]

Targeting metabolic pathways to counter cancer immunotherapy resistance.

Yuki Agarwala, Timothy A Brauns, Ann E Sluder, Mark C Poznansky, Yohannes Gemechu.

Immunotherapies have revolutionized the treatment of certain cancers, but challenges remain in overcoming immunotherapy resistance. Research shows that metabolic modulation of the tumor microenvironment can enhance antitumor immunity. Here, we discuss recent preclinical and clinical evidence for the efficacy of combining metabolic modifiers with immunotherapies. While this combination holds great promise, a few key areas must be addressed, which include identifying the effects of metabolic modifiers on immune cell metabolism, the putative biomarkers of therapeutic efficacy, the efficacy of modifiers on tumors harboring metabolic heterogeneity, and the potential development of resistance due to tumor reliance on alternative metabolic pathways. We propose solutions to these problems and posit that assessing these parameters is crucial for considering the potential of metabolic modifiers in sensitizing tumors to immunotherapies.

Keywords: immunotherapy; immunotherapy resistance; metabolic reprogramming

DOI: https://doi.org/10.1016/j.it.2024.05.006

APMIS. 2024 Jun 14.

Unraveling the intricacies of cancer-associated fibroblasts: a comprehensive review on metabolic reprogramming and tumor microenvironment crosstalk.

Sana Ahuja, Niti Sureka, Sufian Zaheer.

Cancer-associated fibroblasts (CAFs) are crucial component of tumor microenvironment (TME) which undergo significant phenotypic changes and metabolic reprogramming, profoundly impacting tumor growth. This review delves into CAF plasticity, diverse origins, and the molecular mechanisms driving their continuous activation. Emphasis is placed on the intricate bidirectional crosstalk between CAFs and tumor cells, promoting cancer cell survival, proliferation, invasion, and immune evasion. Metabolic reprogramming, a cancer hallmark, extends beyond cancer cells to CAFs, contributing to the complex metabolic interplay within the TME. The 'reverse Warburg effect' in CAFs mirrors the Warburg effect, involving the export of high-energy substrates to fuel cancer cells, supporting their rapid proliferation. Molecular regulations by key players like p53, Myc, and K-RAS orchestrate this metabolic adaptation. Understanding the metabolic symbiosis between CAFs and tumor cells opens avenues for targeted therapeutic strategies to disrupt this dynamic crosstalk. Unraveling CAF-mediated metabolic reprogramming provides valuable insights for developing novel anticancer therapies. This comprehensive review consolidates current knowledge, shedding light on CAFs' multifaceted roles in the TME and offering potential targets for future therapies.

Keywords: Tumor microenvironment; Warburg effect; cancer‐associated fibroblasts; metabolic reprogramming

DOI: https://doi.org/10.1111/apm.13447

Curr Gene Ther. 2024 Jun 10.

The Role and Treatment Strategies of Ammonia-Related Metabolism in Tumor Microenvironment.

Qizhen Ye, Dan Li, Yi Zou, Ying Yuan.

Tumor cells achieve their adaptability through various metabolic reprogramming processes. Among them, ammonia, as a traditional metabolic waste, plays an increasingly important role in the tumor microenvironment along with its associated metabolites. Other cells in the microenvironment can also reshape the immune status of the microenvironment by regulating ammonia-related metabolism, and targeting this metabolic aspect has emerged as a potential strategy for tumor treatment. In this study, we have systematically reviewed the source and destination of ammonia in tumor cells, as well as the links between ammonia and other biological processes. We have also analyzed the ammonia-related metabolic regulation of other cells (including T cells, macrophages, dendritic cells, natural killer cells, myeloid-derived suppressor cells, and stromal cells) in the tumor microenvironment, and summarized the tumor treatment methods that target this metabolism. Through ammonia-related metabolic reprogramming, tumor cells obtain the energy they need for rapid growth and proliferation. Multiple immune cells and stromal cells in the microenvironment also interact with each other through this metabolic regulation, ultimately leading to immune suppression. Despite the heterogeneity of tumors and the complexity of cellular functions, further research into therapeutic interventions targeting ammonia-related metabolism is warranted. This review has focused on the role and regulation of ammonia-related metabolism in tumor cells and other cells in the microenvironment, and highlighted the efficacy and prospects of targeted ammonia-related metabolism therapy.

Keywords: Ammonia; Anti-tumor therapy; Immune cell; Metabolism; Reprogramming; Tumor microenvironment

DOI: https://doi.org/10.2174/0115665232301222240603100840

Redox Biol. 2024 May 25. pii: S2213-2317(24)00187-3. [Epub ahead of print]74 103209

Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression.

Xuyu Gu, Yifei Zhu, Jincheng Su, Sheng Wang, Xiangyu Su, Xu Ding, Lei Jiang, Xiang Fei, Wentian Zhang.

Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.

Keywords: Cancer-associated fibroblasts; Lung cancer; Tumor microenvironment; Tumor progression; Tumor-associated macrophages

DOI: https://doi.org/10.1016/j.redox.2024.103209

J Bone Oncol. 2024 Jun;46 100609

Adipocytes and metabolism: Contributions to multiple myeloma.

Heather Fairfield, Michelle Karam, Allyson Schimelman, Ya-Wei Qiang, Michaela R Reagan.

Obesity contributes to many cancers, including breast cancer and multiple myeloma, two cancers that often colonize the bone marrow (BM). Obesity often causes metabolic disease, but at the cellular level, there is uncertainty regarding how these shifts affect cellular phenotypes. Evidence is building that different types of fuel affect tumor cell metabolism, mitochondrial function, and signaling pathways differently, but tumor cells are also flexible and adapt to less-than ideal metabolic conditions, suggesting that single-pronged attacks on tumor metabolism may not be efficacious enough to be effective clinically. In this review, we describe the newest research at the pre-clinical level on how tumor metabolic pathways and energy sources affect cancer cells, with a special focus on multiple myeloma (MM). We also describe the known forward-feedback loops between bone marrow adipocytes (BMAds) and local tumor cells that support tumor growth. We describe how metabolic targets and transcription factors related to fatty acid (FA) oxidation, FA biosynthesis, glycolysis, oxidative phosphorylation (OXPHOS), and other pathways hold great promise as new vulnerabilities in myeloma cells. Specifically, we describe the importance of the acetyl-CoA synthetase (ACSS) and the acyl-CoA synthetase long chain (ACSL) families, which are both involved in FA metabolism. We also describe new data on the importance of lactate metabolism and lactate transporters in supporting the growth of tumor cells in a hypoxic BM microenvironment. We highlight new data showing the dependency of myeloma cells on the mitochondrial pyruvate carrier (MPC), which transports pyruvate to the mitochondria to fuel the tricarboxylic acid (TCA) cycle and electron transport chain (ETC), boosting OXPHOS. Inhibiting the MPC affects myeloma cell mitochondrial metabolism and growth, and synergizes with proteosome inhibitors in killing myeloma cells. We also describe how metabolic signaling pathways intersect established survival and proliferation pathways; for example, the fatty acid binding proteins (FABPs) affect MYC signaling and support growth, survival, and metabolism of myeloma cells. Our goal is to review the current the field so that novel, metabolic-focused therapeutic interventions and treatments can be imagined, developed and tested to decrease the burden of MM and related cancers.

Keywords: Adipocytes; Drug resistance; Fatty acids; Metabolism; Multiple myeloma

DOI: https://doi.org/10.1016/j.jbo.2024.100609

bioRxiv. 2024 Jun 01. pii: 2023.08.25.554830. [Epub ahead of print]

Histone Lactylation Drives CD8 T Cell Metabolism and Function.

Deblina Raychaudhuri, Pratishtha Singh, Mercedes Hennessey, Bidisha Chakraborty, Aminah J Tannir, Abel Trujillo-Ocampo, Jin Seon Im, Sangeeta Goswami.

The activation and functional differentiation of CD8 T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification (hPTM); however, the relevance of histone lactylation in the context of CD8 T cell activation and function is not known. Here, we show the enrichment of H3K18-lactylation (H3K18la) and H3K9-lactylation (H3K9la) in human and murine CD8 T cells which act as transcription initiators of key genes regulating CD8 T cell phenotype and function. Further, we note distinct impacts of H3K18la and H3K9la on CD8 T cell subsets linked to their specific metabolic profiles. Importantly, we demonstrate that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways regulates CD8 T cell effector function including anti-tumor immunity in preclinical models. Overall, our study uncovers the unique contributions of H3K18la and H3K9la in modulating CD8 T cell phenotype and function intricately associated with metabolic state.

DOI: https://doi.org/10.1101/2023.08.25.554830