bims-tumime 2023-11-26 papers

Issue of 2023–11–26
six papers selected by
Alex Muir, University of Chicago

Cancer Discov. 2023 Nov 22. OF1

Vitamin B5 Supports Oncogenic Metabolism in MYC-Driven Breast Cancer.

Pantothetic acid is required for metabolic activity that supports MYC-driven breast tumor growth.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-185

Cancer Immunol Res. 2023 Nov 21.

A metabolic axis of immune intractability.

Dominique C Hinshaw, Meet Patel, Lalita A Shevde.

Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are re-enacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0433

Oncogene. 2023 Nov 23.

DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression.

Favour A Akinjiyan, Zainab Ibitoye, Peinan Zhao, Leah P Shriver, Gary J Patti, Gregory D Longmore, Katherine C Fuh.

Ovarian cancer has poor survival outcomes particularly for advanced stage, metastatic disease. Metastasis is promoted by interactions of stromal cells, such as cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), with tumor cells. CAFs play a key role in tumor progression by remodeling the TME and extracellular matrix (ECM) to result in a more permissive environment for tumor progression. It has been shown that fibroblasts, in particular myofibroblasts, utilize metabolism to support ECM remodeling. However, the intricate mechanisms by which CAFs support collagen production and tumor progression are poorly understood. In this study, we show that the fibrillar collagen receptor, Discoidin Domain Receptor 2 (DDR2), promotes collagen production in human and mouse omental CAFs through arginase activity. CAFs with high DDR2 or arginase promote tumor colonization in the omentum. In addition, DDR2-depleted CAFs had decreased ornithine levels leading to decreased collagen production and polyamine levels compared to WT control CAFs. Tumor cell invasion was decreased in the presence CAF conditioned media (CM) depleted of DDR2 or arginase-1, and this invasion defect was rescued in the presence of CM from DDR2-depleted CAFs that constitutively overexpressed arginase-1. Similarly, the addition of exogenous polyamines to CM from DDR2-depleted CAFs led to increased tumor cell invasion. We detected SNAI1 protein at the promoter region of the arginase-1 gene, and DDR2-depleted CAFs had decreased levels of SNAI1 protein at the arginase-1 promoter region. Furthermore, high stromal arginase-1 expression correlated with poor survival in ovarian cancer patients. These findings highlight how DDR2 regulates collagen production by CAFs in the tumor microenvironment by controlling the transcription of arginase-1, and CAFs are a major source of arginase activity and L-arginine metabolites in ovarian cancer models.

DOI: https://doi.org/10.1038/s41388-023-02884-3

J Biol Chem. 2023 Nov 20. pii: S0021-9258(23)02513-9. [Epub ahead of print] 105485

Metabolic reprogramming driven by EZH2 inhibition depends on cell-matrix interactions.

Teresa W-M Fan, Jahid M M Islam, Richard M Higashi, Penghui Lin, Christine F Brainson, Andrew N Lane.

EZH2 (Enhancer of Zeste Homolog 2), a subunit of Polycomb Repressive Complex 2 (PRC2), catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), which represses expression of genes. It also has PRC2-independent functions, including transcriptional coactivation of oncogenes, and is frequently overexpressed in lung cancers. Clinically, EZH2 inhibition can be achieved with the FDA-approved drug EPZ-6438 (tazemetostat). To realize the full potential of EZH2 blockade, it is critical to understand how cell-cell/cell-matrix interactions present in three-dimensional (3D) tissue and cell culture systems influences this blockade in terms of growth-related metabolic functions. Here, we show that EZH2 suppression reduced growth of human lung adenocarcinoma A549 cells in two-dimensional (2D) cultures but stimulated growth in 3D culture. To understand the metabolic underpinnings, we employed [13C6]-glucose Stable Isotope-Resolved Metabolomics (SIRM) to determine the effect of EZH2 suppression on metabolic networks in 2D versus 3D A549 cultures. The Krebs cycle, neoribogenesis, γ-aminobutyrate (GAB) metabolism, and salvage synthesis of purine nucleotides were activated by EZH2 suppression in 3D spheroids but not in 2D cells, consistent with the growth effect. Using simultaneous 2H7-glucose + 13C5,15N2-Gln tracers and EPZ-6438 inhibition of H3 trimethylation, we delineated the effects on the Krebs cycle, γ-aminobutyrate metabolism, gluconeogenesis, and purine salvage to be PRC2 dependent. Furthermore, the growth/metabolic effects differed for mouse Matrigel versus self-produced A549 extracellular matrix. Thus, our findings highlight the importance of the presence and nature of extracellular matrix in studying the function of EZH2 and its inhibitors in cancer cells for modeling the in vivo outcomes.

Keywords: EZH2; Stable Isotope-Resolved Metabolomics; extracellular matrix; glucose/glutamine metabolism; spheroids

DOI: https://doi.org/10.1016/j.jbc.2023.105485

Biochim Biophys Acta Rev Cancer. 2023 Nov 20. pii: S0304-419X(23)00171-3. [Epub ahead of print] 189022

Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity.

Sirui Zhang, Xiaozhen Zhang, Hanshen Yang, Tingbo Liang, Xueli Bai.

Glucose metabolism is essential for the activation, differentiation and function of T cells and proper glucose metabolism is required to maintain effective T cell immunity. Dysregulation of glucose metabolism is a hallmark of cancer, and the tumour microenvironment (TME2) can create metabolic barriers in T cells that inhibit their anti-tumour immune function. Targeting glucose metabolism is a promising approach to improve the capacity of T cells in the TME. The efficacy of common immunotherapies, such as immune checkpoint inhibitors (ICIs3) and adoptive cell transfer (ACT4), can be limited by T-cell function, and the treatment itself can affect T-cell metabolism. Therefore, understanding the relationship between immunotherapy and T cell glucose metabolism helps to achieve more effective anti-tumour therapy. In this review, we provide an overview of T cell glucose metabolism and how T cell metabolic reprogramming in the TME regulates anti-tumour responses, briefly describe the metabolic patterns of T cells during ICI and ACT therapies, which suggest possible synergistic strategies.

Keywords: Adoptive cell transfer therapy; Glucose metabolism; Immune checkpoint; Metabolic reprogramming; T cell; Tumour microenvironment

DOI: https://doi.org/10.1016/j.bbcan.2023.189022

Cell Signal. 2023 Nov 20. pii: S0898-6568(23)00398-4. [Epub ahead of print]114 110983

Knockdown of SQLE promotes CD8+ T cell infiltration in the tumor microenvironment.

Jun Wu, Weibin Hu, Wenhui Yang, Yihao Long, Kaizhao Chen, Fugui Li, Xiaodong Ma, Xun Li.

Cholesterol biosynthesis and metabolism are critical aspects that shape the process of tumor development and associated microenvironmental conditions owing to the ability of cholesterol to drive tumor growth and invasion. Squalene Epoxidase (SQLE) is the second rate-limiting enzyme involved in the synthesis of cholesterol. The functional role of SQLE within the tumor microenvironment, however, has yet to be established. Here we show that SQLE is distinctively expressed across most types of cancer, and the expression level is highly correlated with tumor mutation burden and microsatellite instability. Accordingly, SQLE was identified as a prognostic risk factor in cancer patients. In addition, we observed a negative correlation between SQLE expression and immune cell infiltration across multiple cancers, and murine xenograft model further confirmed that SQLE knockdown was associated with enhanced intratumoral CD8+ T cell infiltration. Using next-generation sequencing, we identified 410 genes distinctively expressed in tumors exhibiting SQLE inhibition. KEGG and GO analysis further verified that SQLE altered the immune response in the tumor microenvironment. Furthermore, we found that the metabolism and translation of proteins is the main binding factor with SQLE. Our findings ascertain that SQLE is a potential target in multiple cancers and suppressing SQLE establishes an essential mechanism for shaping tumor microenvironment.

Keywords: CD8(+) T cell; Cholesterol; SQLE; Tumor microenvironment

DOI: https://doi.org/10.1016/j.cellsig.2023.110983