bims-mecami 2024-04-21 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–04–21
nine papers selected by
Oltea Sampetrean, Keio University

25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages.
Regulation of fatty acid delivery to metastases by tumor endothelium.
Microglia and macrophage metabolism: a regulator of cerebral gliomas.
The essential link: How STAT3 connects tumor metabolism to immunity.
Association between metabolic reprogramming and immune regulation in digestive tract tumors.
Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities.
Diet and Cancer Metabolism.
Lactate and Lactylation: Behind the Development of Tumors.
Macropinocytosis at the crossroad between nutrient scavenging and metabolism in cancer.

Immunity. 2024 Apr 12. pii: S1074-7613(24)00142-0. [Epub ahead of print]

25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages.

Jun Xiao, Shuang Wang, Longlong Chen, Xinyu Ding, Yuanhao Dang, Mingshun Han, Yuxiao Zheng, Huan Shen, Sifan Wu, Mingchang Wang, Dan Yang, Na Li, Chen Dong, Miao Hu, Chen Su, Weiyun Li, Lijian Hui, Youqiong Ye, Huiru Tang, Bin Wei, Hongyan Wang.

  Macrophages are critical to turn noninflamed "cold tumors" into inflamed "hot tumors". Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25Hhi subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8+ T cell surveillance and anti-tumor response.

Keywords:  25-hydroxycholesterol; AMPK; CH25H; M2-like macrophage; STAT6; cholesterol matabolism; oxysterol; tumor immunotherapy; tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.immuni.2024.03.021
bioRxiv. 2024 Apr 03. pii: 2024.04.02.587724. [Epub ahead of print]

Regulation of fatty acid delivery to metastases by tumor endothelium.

Deanna N Edwards, Shan Wang, Wenqiang Song, Laura C Kim, Verra M Ngwa, Yoonha Hwang, Kevin C Ess, Mark R Boothby, Jin Chen.

Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth 1 . Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs but impair the cytotoxicity of T cells in the tumor microenvironment (TME) 2, 3 , thereby supporting metastatic progression. However, despite the important role of FA in metastatic outgrowth, the regulation of intratumoral FA is poorly understood. In this report, we show that tumor endothelium actively promotes tumor growth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. This process uses transendothelial fatty acid transport via endosome cargo trafficking in a mechanism that requires mTORC1 activity. Thus, tumor burden was significantly reduced upon endothelial-specific targeted deletion of Raptor, a unique component of the mTORC1 complex (Rptor ECKO ). In vivo trafficking of a fluorescent palmitic acid analog to tumor cells and T cells was reduced in Rptor ECKO lung metastatic tumors, which correlated with improved markers of T cell cytotoxicity. Combination of anti-PD1 with RAD001/everolimus, at a low dose that selectively inhibits mTORC1 in endothelial cells 4 , impaired FA uptake in T cells and reduced metastatic disease, corresponding to improved anti-tumor immunity. These findings describe a novel mechanism of transendothelial fatty acid transfer into the TME during metastatic outgrowth and highlight a target for future development of therapeutic strategies.

DOI: https://doi.org/10.1101/2024.04.02.587724
Cell Biosci. 2024 Apr 17. 14(1): 49

Microglia and macrophage metabolism: a regulator of cerebral gliomas.

Yue Deng, Qinyan Chen, Chao Wan, Yajie Sun, Fang Huang, Yan Hu, Kunyu Yang.

  Reciprocal interactions between the tumor microenvironment (TME) and cancer cells play important roles in tumorigenesis and progression of glioma. Glioma-associated macrophages (GAMs), either of peripheral origin or representing brain-intrinsic microglia, are the majority population of infiltrating immune cells in glioma. GAMs, usually classified into M1 and M2 phenotypes, have remarkable plasticity and regulate tumor progression through different metabolic pathways. Recently, research efforts have increasingly focused on GAMs metabolism as potential targets for glioma therapy. This review aims to delineate the metabolic characteristics of GAMs within the TME and provide a summary of current therapeutic strategies targeting GAMs metabolism in glioma. The goal is to provide novel insights and therapeutic pathways for glioma by highlighting the significance of GAMs metabolism.

Keywords:  Glioma; Glioma-associated macrophages; Metabolism; Targeted therapy

DOI:  https://doi.org/10.1186/s13578-024-01231-7
Biochim Biophys Acta Gene Regul Mech. 2024 Apr 16. pii: S1874-9399(24)00024-5. [Epub ahead of print] 195028

The essential link: How STAT3 connects tumor metabolism to immunity.

Shu Zhong, Jingjing Tong.

  Immunotherapy is a promising and long-lasting tumor treatment method, but it is challenged by the complex metabolism of tumors. To optimize immunotherapy, it is essential to further investigate the key proteins that regulate tumor metabolism and immune response. STAT3 plays a crucial role in regulating tumor dynamic metabolism and affecting immune cell function by responding to various cytokines and growth factors, which can be used as a potential target for immunotherapy. This review focuses on the crosstalk between STAT3 and tumor metabolism (including glucose, lipid, and amino acid metabolism) and its impact on the differentiation and function of immune cells such as T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), and reveals potential treatment strategies.

Keywords:  Immune cell; Immunotherapy; Metabolism; STAT3; Tumor

DOI:  https://doi.org/10.1016/j.bbagrm.2024.195028
Oncol Res Treat. 2024 Apr 18.

Association between metabolic reprogramming and immune regulation in digestive tract tumors.

Jiafeng Liu, Tianxiao Wang, Wenxin Zhang, Yuxin Huang, Xinhai Wang, Qunyi Li.

BACKGROUND: The cancers of the digestive tract, including colorectal cancer (CRC), gastric cancer (GC) and Esophageal cancer (ESCA), are part of the most common cancers as well as one of the most important leading causes of cancer death worldwide.
SUMMARY: Despite the emergence of immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) in the past decade, offering renewed optimism in cancer treatment, only a fraction of patients derive benefit from these therapies. This limited efficacy may stem from tumor heterogeneity and the impact of metabolic reprogramming on both tumor cells and immune cells within the tumor microenvironment (TME). The metabolic reprogramming of glucose, lipids, amino acids, and other nutrients represents a pivotal hallmark of cancer, serving to generate energy, reducing-equivalent and biological macromolecule, thereby fostering tumor proliferation and invasion. Significantly, the metabolic reprogramming of tumor cells can orchestrate changes within the TME, rendering patients unresponsive to immunotherapy.
KEY MESSAGES: In this review, we predominantly encapsulate recent strides on metabolic reprogramming among digestive tract cancer, especially CRC, in the TME with a focus on how these alterations influence antitumor immunity. Additionally, we deliberate on potential strategies to address these abnormities in metabolic pathways and the viability of combined therapy within the realm of anticancer immunotherapy.

DOI: https://doi.org/10.1159/000538659
Int J Biol Sci. 2024 ;20(6): 2044-2071

Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities.

Wen Jiang, Wei-Lin Jin, A-Man Xu.

  Cholesterol is crucial for cell survival and growth, and dysregulation of cholesterol homeostasis has been linked to the development of cancer. The tumor microenvironment (TME) facilitates tumor cell survival and growth, and crosstalk between cholesterol metabolism and the TME contributes to tumorigenesis and tumor progression. Targeting cholesterol metabolism has demonstrated significant antitumor effects in preclinical and clinical studies. In this review, we discuss the regulatory mechanisms of cholesterol homeostasis and the impact of its dysregulation on the hallmarks of cancer. We also describe how cholesterol metabolism reprograms the TME across seven specialized microenvironments. Furthermore, we discuss the potential of targeting cholesterol metabolism as a therapeutic strategy for tumors. This approach not only exerts antitumor effects in monotherapy and combination therapy but also mitigates the adverse effects associated with conventional tumor therapy. Finally, we outline the unresolved questions and suggest potential avenues for future investigations on cholesterol metabolism in relation to cancer.

Keywords:  antitumor immunity; cholesterol homeostasis; drug repurposing; metastasis; statin; tumor microenvironment

DOI:  https://doi.org/10.7150/ijbs.92274
Cold Spring Harb Perspect Med. 2024 Apr 15. pii: a041549. [Epub ahead of print]

Diet and Cancer Metabolism.

Jason W Locasale, Marcus D Goncalves, Maira Di Tano, Guillermo Burgos-Barragan.

Diet and exercise are modifiable lifestyle factors known to have a major influence on metabolism. Clinical practice addresses diseases of altered metabolism such as diabetes or hypertension by altering these factors. Despite enormous public interest, there are limited defined diet and exercise regimens for cancer patients. Nevertheless, the molecular basis of cancer has converged over the past 15 years on an essential role for altered metabolism in cancer. However, our understanding of the molecular mechanisms that underlie the impact of diet and exercise on cancer metabolism is in its very early stages. In this work, we propose conceptual frameworks for understanding the consequences of diet and exercise on cancer cell metabolism and tumor biology and also highlight recent developments. By advancing our mechanistic understanding, we also discuss actionable ways that such interventions could eventually reach the mainstay of both medical oncology and cancer control and prevention.

DOI: https://doi.org/10.1101/cshperspect.a041549
Cancer Lett. 2024 Apr 17. pii: S0304-3835(24)00289-1. [Epub ahead of print] 216896

Lactate and Lactylation: Behind the Development of Tumors.

Enci Dai, Wei Wang, Yingying Li, Defeng Ye, Yanli Li.

There is growing evidence that lactate can have a wide range of biological impacts in addition to being a waste product of metabolism. Because of the Warburg effect, tumors generate lots of lactate, which create a tumor microenvironment (TME) with low nutrition, hypoxia, and low pH. As a result, the immunosuppressive network is established to gain immune escape potential and regulate tumor growth. Consequently, the tumor lactate pathway is emerging as a possible therapeutic target for tumor. Importantly, Zhao et al. first discovered histone lysine lactylation (Kla) in 2019, which links gene regulation to cell metabolism through dysmetabolic activity and epigenetic modifications, influencing TME and tumor development. Therefore, the aim of this paper is to explore the effects of lactate and lactylation on the TME and tumors, and provide theoretical basis for further research on potential therapeutic targets and biomarkers, with the view to providing new ideas and methods for tumor treatment and prognosis evaluation.

DOI: https://doi.org/10.1016/j.canlet.2024.216896
Curr Opin Cell Biol. 2024 Apr 15. pii: S0955-0674(24)00038-3. [Epub ahead of print]88 102359

Macropinocytosis at the crossroad between nutrient scavenging and metabolism in cancer.

Elena Rainero.

Macropinocytosis (MP), the actin-dependent bulk uptake of extracellular fluids, plays a central role in nutrient scavenging, allowing cancer cells to sustain their growth in the hypoxic and nutrient-deprived microenvironment often found in solid tumours. The lack of soluble nutrients and several oncogenic signalling pathways, with RAS being the most studied, push MP-dependent internalisation of extracellular proteins, which are then digested in the lysosomes, replenishing the intracellular nutrient pools. This review will highlight recent advances in understanding how MP is regulated in hypoxic cancers, how it impinges on chemoresistance, and how different MP cargos facilitate tumour growth. Finally, I will highlight the crosstalk between MP and extracellular matrix receptors.

DOI: https://doi.org/10.1016/j.ceb.2024.102359