bims-tumime 2023-12-10 papers

Issue of 2023–12–10
five papers selected by
Alex Muir, University of Chicago

Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00415-1. [Epub ahead of print]35(12): 2093-2094

Fructose sweetens the adipocyte-T cell alliance against tumors.

Dietary fructose is implicated in tumorigenesis, but whether dietary fructose regulates antitumor immunity remains elusive. In this issue of Cell Metabolism, Zhang et al. show that dietary fructose promotes adipocyte-derived leptin production, which attenuates terminal exhaustion programming and boosts the effector function of CD8+ T cells for improved tumor control.

DOI: https://doi.org/10.1016/j.cmet.2023.11.004

APL Bioeng. 2023 Dec;7(4): 046116

Endothelial cells metabolically regulate breast cancer invasion toward a microvessel.

Matthew L Tan, Niaa Jenkins-Johnston, Sarah Huang, Brittany Schutrum, Sandra Vadhin, Abhinav Adhikari, Rebecca M Williams, Warren R Zipfel, Jan Lammerding, Jeffrey D Varner, Claudia Fischbach.

Breast cancer metastasis is initiated by invasion of tumor cells into the collagen type I-rich stroma to reach adjacent blood vessels. Prior work has identified that metabolic plasticity is a key requirement of tumor cell invasion into collagen. However, it remains largely unclear how blood vessels affect this relationship. Here, we developed a microfluidic platform to analyze how tumor cells invade collagen in the presence and absence of a microvascular channel. We demonstrate that endothelial cells secrete pro-migratory factors that direct tumor cell invasion toward the microvessel. Analysis of tumor cell metabolism using metabolic imaging, metabolomics, and computational flux balance analysis revealed that these changes are accompanied by increased rates of glycolysis and oxygen consumption caused by broad alterations of glucose metabolism. Indeed, restricting glucose availability decreased endothelial cell-induced tumor cell invasion. Our results suggest that endothelial cells promote tumor invasion into the stroma due, in part, to reprogramming tumor cell metabolism.

DOI: https://doi.org/10.1063/5.0171109

Curr Opin Biotechnol. 2023 Dec 05. pii: S0958-1669(23)00132-5. [Epub ahead of print]85 103022

The posttranslational regulation of amino acid transporters is critical for their function in the tumor microenvironment.

Jessica C Koe, Seth J Parker.

Amino acid transporters (AATs) facilitate nutrient uptake and nutrient exchange between cancer and stromal cells. The posttranslational modification (PTM) of transporters is an important mechanism that tumor-associated cells use to dynamically regulate their function and stability in response to microenvironmental cues. In this review, we summarize recent findings that demonstrate the significance of N-glycosylation, phosphorylation, and ubiquitylation for the function of AATs. We also highlight powerful approaches that hijack the PTM machinery that could be used as therapeutics or tools to modulate transporter activity.

DOI: https://doi.org/10.1016/j.copbio.2023.103022

Arch Pharm Res. 2023 Dec 07.

Targeting dysregulated lipid metabolism in the tumor microenvironment.

Do-Hee Kim, Na-Young Song, Hyungshin Yim.

The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process. Regulation of lipid metabolizing enzymes has been shown to modulate cancer development and to avoid resistance to anticancer drugs in tumors and the TME. Because of this, understanding the metabolic reprogramming associated with oncogenic progression is important to develop strategies for cancer treatment. Recent advances provide insight into fundamental mechanisms and the connections between altered lipid metabolism and tumorigenesis. In this review, we explore alterations to lipid metabolism and the pivotal factors driving lipid metabolic reprogramming, which exacerbate cancer progression. We also shed light on the latest insights and current therapeutic approaches based on small molecular inhibitors and phytochemicals targeting lipid metabolism for cancer treatment. Further investigations are worthwhile to fully understand the underlying mechanisms and the correlation between altered lipid metabolism and carcinogenesis.

Keywords: Cholesterol transport; Lipid uptake; Lipogenesis; Lipolysis; Phytochemical; Tumor microenvironment

DOI: https://doi.org/10.1007/s12272-023-01473-y

Sci Adv. 2023 Dec 08. 9(49): eadf9522

Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.

Chao Chen, Hong Zheng, Edwin M Horwitz, Satomi Ando, Koichi Araki, Peng Zhao, Zhiguo Li, Mandy L Ford, Rafi Ahmed, Cheng-Kui Qu.

Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection-the utilization of pyruvate, a major mitochondrial substrate derived from glucose-was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.

DOI: https://doi.org/10.1126/sciadv.adf9522