bims-mecami 2023-09-10 papers

Issue of 2023–09–10
six papers selected by
Oltea Sampetrean, Keio University

iScience. 2023 Sep 15. 26(9): 107569

Genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer.

Colorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment (TME), which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the TME. These immune cells are generally categorized as M1, with inflammatory and anti-cancer properties, or M2, which promote tumor proliferation and survival. Although the M1/M2 subclassification scheme is strongly influenced by metabolism, the metabolic divergence between the subtypes remains poorly understood. Therefore, we generated a suite of computational models that characterize the M1- and M2-specific metabolic states. Our models show key differences between the M1 and M2 metabolic networks and capabilities. We leverage the models to identify metabolic perturbations that cause the metabolic state of M2 macrophages to more closely resemble M1 cells. Overall, this work increases understanding of macrophage metabolism in CRC and elucidates strategies to promote the metabolic state of anti-tumor macrophages.

Keywords: Cancer; Health informatics; Human genetics; Quantitative genetics

DOI: https://doi.org/10.1016/j.isci.2023.107569

Front Immunol. 2023 ;14 1212695

Crosstalk between autophagy and metabolic regulation of (CAR) T cells: therapeutic implications.

Ahmad Reza Panahi Meymandi, Behnia Akbari, Tahereh Soltantoyeh, Jamshid Hadjati, Daniel J Klionsky, Behnam Badie, Hamid Reza Mirzaei.

Despite chimeric antigen receptor (CAR) T cell therapy's extraordinary success in subsets of B-cell lymphoma and leukemia, various barriers restrict its application in solid tumors. This has prompted investigating new approaches for producing CAR T cells with superior therapeutic potential. Emerging insights into the barriers to CAR T cell clinical success indicate that autophagy shapes the immune response via reprogramming cellular metabolism and vice versa. Autophagy, a self-cannibalization process that includes destroying and recycling intracellular components in the lysosome, influences T cell biology, including development, survival, memory formation, and cellular metabolism. In this review, we will emphasize the critical role of autophagy in regulating and rewiring metabolic circuits in CAR T cells, as well as how the metabolic status of CAR T cells and the tumor microenvironment (TME) alter autophagy regulation in CAR T cells to restore functional competence in CAR Ts traversing solid TMEs.

Keywords: CAR T cell; adoptive cellular therapy (ACT); autophagy; metabolism; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2023.1212695

Life Sci. 2023 Sep 04. pii: S0024-3205(23)00705-1. [Epub ahead of print] 122070

PAICS as a potential target for cancer therapy linking purine biosynthesis to cancer progression.

Anqi Huo, Xiangyang Xiong.

Tumor cells are required to undergo metabolic reprogramming for rapid development and progression, and one of the metabolic characteristics of cancer cells is the excessive synthesis and utilization of nucleotides. Abnormally increased nucleotides and their metabolites not only directly accelerate tumor cell progression but also indirectly act on stromal cells in the tumor microenvironment (TME) via a paracrine manner to regulate tumor progression. Purine nucleotides are mainly produced via de novo nucleotide synthesis in tumor cells; therefore, intervening in their synthesis has emerged as a promising strategy in anti-tumor therapy. De novo purine synthesis is a 10-step reaction catalyzed by six enzymes to synthesize inosine 5-monophosphate (IMP) and subsequently synthesize AMP and GMP. Phosphoribosylaminoimidazole carboxylase/phosphori-bosylaminoimidazole succinocarboxamide synthetase (PAICS) is a bifunctional enzyme that catalyzes de novo purine synthesis. Aberrantly elevated PAICS expression in various tumors is associated with poor prognosis. Evidence suggests that PAICS and its catalytic product, N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR), could inhibit tumor cell apoptosis and promote the growth, epithelial-mesenchymal transition (EMT), invasion, and metastasis by regulating signaling pathways such as pyruvate kinase M2 (PKM2), extracellular signal-related kinases 1 and 2 (ERK1/2), focal adhesion kinase (FAK) and so on. This review summarizes the structure, biological functions and the molecular mechanisms of PAICS in cancer development and discusses its potential to be a target for tumor therapy.

Keywords: Carcinogenesis; De novo purine synthesis; Nucleotide metabolism; PAICS; SAICAR

DOI: https://doi.org/10.1016/j.lfs.2023.122070

bioRxiv. 2023 Aug 22. pii: 2023.08.22.554238. [Epub ahead of print]

Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism.

Veani Fernando, Xunzhen Zheng, Vandana Sharma, Saori Furuta.

HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor associated macrophages (TAMs). While TAMs consist of the immune-stimulatory M1-type and immune-suppressive M2-type, M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1 vs. M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2- TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- vs M2-TAMs is attributed to different availability of BH 4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH 4 precursor, elevates the expression of M1- TAM markers within HER2+ tumors. Here, we show that SEP restores BH 4 levels in M2-TAMs, which then redirects arginine metabolism to NO synthesis and converts M2-TAMs to M1-TAMs. The reprogrammed TAMs exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in metabolic shift of HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.

DOI: https://doi.org/10.1101/2023.08.22.554238

Int J Cancer. 2023 Sep 08.

Glycolysis regulation in tumor-associated macrophages: Its role in tumor development and cancer treatment.

Guangyi Jiang, Junjie Hong, Lu Sun, Haibin Wei, Wangang Gong, Shu Wang, Jianqing Zhu.

Tumor-associated macrophages constitute the main cell population in the tumor microenvironment and play a crucial role in regulating the microenvironment composition. Emerging evidence has revealed that the metabolic profile determines the tumor-associated macrophage phenotype. Tumor-associated macrophage function is highly dependent on glucose metabolism, with glycolysis being the major metabolic pathway. Recent reports have demonstrated diversity in glucose flux of tumor-associated macrophages and complex substance communication with cancer cells. However, how the glucose flux in tumor-associated macrophages connects with glycolysis to influence tumor progression and the tumor microenvironment is still obscure. Moreover, while the development of single-cell sequencing technology allows a clearer and more accurate classification of tumor-associated macrophages, the metabolic profiles of tumor-associated macrophages from the perspective of single-cell omics has not been well summarized. Here, we review the current state of knowledge on glucose metabolism in tumor-associated macrophages and summarize the metabolic profiles of different tumor-associated macrophage subtypes from the perspective of single-cell omics. Additionally, we describe the current strategies targeting glycolysis in tumor-associated macrophages for cancer therapy.

Keywords: glucose metabolism; single-cell omics; targeted cancer therapy; tumor microenvironment; tumor-associated macrophage

DOI: https://doi.org/10.1002/ijc.34711