bims-mecami 2024-11-24 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–11–24
ten papers selected by
Oltea Sampetrean, Keio University

The influence of endothelial metabolic reprogramming on the tumor microenvironment.
Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer.
Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells.
Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.
An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
Dendrimer/Copper(II) Complex-Mediated siRNA Delivery Disrupts Lactate Metabolism to Reprogram the Local Immune Microenvironment against Tumor Growth and Metastasis.
Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment.
Uncovering the protective role of lipid droplet accumulation against acid-induced oxidative stress and cell death in osteosarcoma.
Nanotube-mediated mitochondrial transfer: power to the T cells!

Oncogene. 2024 Nov 20.

The influence of endothelial metabolic reprogramming on the tumor microenvironment.

Kelby Kane, Deanna Edwards, Jin Chen.

Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC's role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.

DOI: https://doi.org/10.1038/s41388-024-03228-5
J Clin Invest. 2024 Nov 19. pii: e177824. [Epub ahead of print]

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily R Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sarah Johnson, Mary McGraw, Matthew Grabowski, Tianyao Lu, Lutz Freytag, Vinod K Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin Lathia.

  The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.

Keywords:  Adaptive immunity; Brain cancer; Immunology; Oncology; Polyamines

DOI:  https://doi.org/10.1172/JCI177824
Mol Cancer. 2024 Nov 21. 23(1): 261

Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer.

Shan Liu, Xingda Zhang, Wenzheng Wang, Xue Li, Xue Sun, Yuqian Zhao, Qi Wang, Yingpu Li, Fangjie Hu, He Ren.

Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt to their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth and contributes to treatment resistance. In primary breast cancer, metabolic shifts such as the Warburg effect and enhanced lipid synthesis are closely linked to chemotherapy failure. Similarly, metastatic lesions often display distinct metabolic profiles that not only sustain tumor growth but also confer resistance to targeted therapies and immunotherapies. The review emphasizes two major aspects: the mechanisms driving metabolic resistance in both primary and metastatic breast cancer, and how the unique metabolic environments in metastatic sites further complicate treatment. By targeting distinct metabolic vulnerabilities at both the primary and metastatic stages, new strategies could improve the efficacy of existing therapies and provide better outcomes for breast cancer patients.

DOI: https://doi.org/10.1186/s12943-024-02165-x
Mol Cancer. 2024 Nov 19. 23(1): 260

Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells.

Mei-Qi Yang, Shu-Ling Zhang, Li Sun, Le-Tian Huang, Jing Yu, Jie-Hui Zhang, Yuan Tian, Cheng-Bo Han, Jie-Tao Ma.

  Immune checkpoint blockade therapy has revolutionized cancer treatment, but resistance remains prevalent, often due to dysfunctional tumor-infiltrating lymphocytes. A key contributor to this dysfunction is mitochondrial dysfunction, characterized by defective oxidative phosphorylation, impaired adaptation, and depolarization, which promotes T cell exhaustion and severely compromises antitumor efficacy. This review summarizes recent advances in restoring the function of exhausted T cells through mitochondria-targeted strategies, such as metabolic remodeling, enhanced biogenesis, and regulation of antioxidant and reactive oxygen species, with the aim of reversing the state of T cell exhaustion and improving the response to immunotherapy. A deeper understanding of the role of mitochondria in T cell exhaustion lays the foundation for the development of novel mitochondria-targeted therapies and opens a new chapter in cancer immunotherapy.

Keywords:  Cancer immunotherapy; Epigenetics; Mitochondria; Mitochondria metabolism; Mitochondrial dynamics; T cell exhaustion

DOI:  https://doi.org/10.1186/s12943-024-02175-9
bioRxiv. 2024 Nov 03. pii: 2024.10.30.621159. [Epub ahead of print]

Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.

Maria Fernanda Forni, Gabriela A Pizzurro, Will Krause, Amanda F Alexander, Kate Bridges, Yiting Xu, Olivia Justynski, Anthony Gabry, Niels Olsen Saraiva Camara, Kathryn Miller-Jensen, Valerie Horsley.

The cellular metabolism of macrophages depends on tissue niches and can control macrophage inflammatory or resolving phenotypes. Yet, the identity of signals within tissue niches that control macrophage metabolism is not well understood. Here, using single-cell RNA sequencing of macrophages in early mouse wounds, we find that, rather than gene expression of canonical inflammatory or resolving polarization markers, metabolic gene expression defines distinct populations of early wound macrophages. Single-cell secretomics and transcriptomics identify inflammatory and resolving cytokines expressed by early wound macrophages, and we show that these signals drive metabolic inputs and mitochondrial metabolism in an age-dependent manner. We show that aging alters the metabolome of early wound macrophages and rewires their metabolism from mitochondria to glycolysis. We further show that macrophage-derived Chi3l3 and IGF-1 can induce metabolic inputs and mitochondrial mass/metabolism in aged and bone marrow-derived macrophages. Together, these findings reveal that macrophage-derived signals drive the mitochondrial metabolism of macrophages within early wounds in an age-dependent manner and have implications for inflammatory diseases, chronic injuries, and age-related inflammatory diseases.
In Brief: This study reveals that macrophage subsets in early inflammatory stages of skin wound healing are defined by their metabolic profiles rather than polarization phenotype. Using single-cell secretomics, we establish key macrophage cytokines that comprise the in vivo wound niche and drive mitochondrial-based metabolism. Aging significantly alters macrophage heterogeneity and increases glycolytic metabolism, which can be restored to OxPHOS-based metabolism with young niche cytokines. These findings highlight the importance of the tissue niche in driving macrophage phenotypes, with implications for aging-related impairments in wound healing.
Highlights: Single cell transcriptional analysis reveals that reveals that metabolic gene expression identifies distinct macrophage populations in early skin wounds.Single-cell secretomic data show that young macrophages contribute to the wound bed niche by secreting molecules such as IGF-1 and Chi3l3.Old wound macrophages display altered metabolomics, elevated glycolytic metabolism and glucose uptake, and reduced lipid uptake and mitochondrial mass/metabolism.Chi3l3 but not IGF-1 secretion is altered in macrophages in an age dependent manner.Chi3l3 can restore mitochondrial mass/metabolism in aged macrophages.

DOI: https://doi.org/10.1101/2024.10.30.621159
bioRxiv. 2024 Nov 03. pii: 2024.10.31.621317. [Epub ahead of print]

An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.

Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Althea Waldhart, Kelly H Sokol, Cameron J Lee, Samuel R Daniels, Joseph Longo, Amy Johnson, Ryan D Sheldon, Russell G Jones, Evan C Lien.

Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation 1-3 . Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors 4-7 . Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo . Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.

DOI: https://doi.org/10.1101/2024.10.31.621317
Biomacromolecules. 2024 Nov 21.

Dendrimer/Copper(II) Complex-Mediated siRNA Delivery Disrupts Lactate Metabolism to Reprogram the Local Immune Microenvironment against Tumor Growth and Metastasis.

Yue Gao, Aiyu Li, Yanying Li, Honghua Guo, Liangyu He, Kangan Li, Dzmitry Shcharbin, Xiangyang Shi, Mingwu Shen.

Solid tumors reprogram metabolic pathways to meet their biosynthesis demands, resulting in elevated levels of metabolites in the tumor microenvironment (TME), including lactate. Excessive accumulation and active transportation of lactate within the TME drives tumor progression, metastasis, and immunosuppression. Interruption of TME lactate metabolism is expected to restore antitumor responses and sensitize tumor immunotherapy. Herein, we developed phenylboronic acid- and pyridine-modified poly(amidoamine) dendrimer/copper(II) (Cu(II)) complexes, namely, D-Cu complexes, to deliver monocarboxylate transporter 4 siRNA (siMCT4) and disrupt the tumor lactate shuttle. The D-Cu complexes are shown to have a Cu(II)-mediated chemodynamic effect and T1-weighted magnetic resonance imaging potential (r1 relaxivity = 1.19 mM-1 s-1), enabling effective siMCT4 delivery to inhibit lactate efflux within cancer cells. In combination with a CD11b immune agonist, the treatment of D-Cu/siMCT4 polyplexes in a mouse breast tumor model alleviates local TME immunosuppression, leading to excellent inhibition of both primary tumor growth and lung metastasis.

DOI: https://doi.org/10.1021/acs.biomac.4c01249
Nat Immunol. 2024 Nov 18.

Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment.

Ruoyan Li, Johanna Strobl, Elizabeth F M Poyner, Aya Balbaa, Fereshteh Torabi, Pavel V Mazin, Nana-Jane Chipampe, Emily Stephenson, Ciro Ramírez-Suástegi, Vijaya Baskar Mahalingam Shanmugiah, Louis Gardner, Bayanne Olabi, Rowen Coulthard, Rachel A Botting, Nina Zila, Elena Prigmore, Nusayhah H Gopee, Marta A Chroscik, Efpraxia Kritikaki, Justin Engelbert, Issac Goh, Hon Man Chan, Harriet F Johnson, Jasmine Ellis, Victoria Rowe, Win Tun, Gary Reynolds, Dexin Yang, April Rose Foster, Laure Gambardella, Elena Winheim, Chloe Admane, Benjamin Rumney, Lloyd Steele, Laura Jardine, Julia Nenonen, Keir Pickard, Jennifer Lumley, Philip Hampton, Simeng Hu, Fengjie Liu, Xiangjun Liu, David Horsfall, Daniela Basurto-Lozada, Louise Grimble, Chris M Bacon, Sophie C Weatherhead, Hanna Brauner, Yang Wang, Fan Bai, Nick J Reynolds, Judith E Allen, Constanze Jonak, Patrick M Brunner, Sarah A Teichmann, Muzlifah Haniffa.

Cutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (TH2) cell-immune gene programs by malignant CTCL cells and modeling of the tumor microenvironment to support their survival. We identified MHC-II+ fibroblasts and dendritic cells that can maintain TH2 cell-like tumor cells. CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. Finally, we validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL.

DOI: https://doi.org/10.1038/s41590-024-02018-1
Biochim Biophys Acta Mol Basis Dis. 2024 Nov 18. pii: S0925-4439(24)00570-2. [Epub ahead of print]1871(2): 167576

Uncovering the protective role of lipid droplet accumulation against acid-induced oxidative stress and cell death in osteosarcoma.

Cortini Margherita, Ilieva Elizabeta, Massari Stefania, Bettini Giuliano, Avnet Sofia, Baldini Nicola.

  Extracellular acidosis stemming from altered tumor metabolism promotes cancer progression by enabling tumor cell adaptation to the hostile microenvironment. In osteosarcoma, we have previously shown that acidosis increases tumor cell survival alongside substantial lipid droplet accumulation. In this study, we explored the role of lipid droplet formation in mitigating cellular stress induced by extracellular acidosis in osteosarcoma cells, thereby enhancing tumor survival during progression. Specifically, we examined how lipid droplets shield against reactive oxygen species induced by extracellular acidosis. We demonstrated that lipid droplet biogenesis is critical for acid-exposed tumor cell survival, as it starts shortly after acid exposure (24 h) and inversely correlates with ROS levels (DCFH-DA assay), lipid peroxidation (Bodipy assay), and the antioxidant response, as also revealed by NRF2 transcript. Additionally, extracellular metabolites, such as lactate, and interaction with mesenchymal stromal cells within the tumor microenvironment intensify lipid droplet build-up in osteosarcoma cells. Critically, upon targeting two key proteins implicated in LD formation - PLIN2 and DGAT1 - cell viability significantly declined while ROS production escalated. In summary, our findings underscore the vital reliance of acid-exposed tumor cells on lipid droplet formation to scavenge oxidative stress. We conclude that the rewiring of lipid metabolism driven by microenvironmental cues is of paramount importance for the survival of metabolically altered osteosarcoma cells in acidic condition. Overall, we suggest that targeting key members of lipid droplet biogenesis may eradicate more aggressive and resistant tumor cells, uncovering potential new treatment strategies for osteosarcoma.

Keywords:  Acidosis; Lipid droplets; Osteosarcoma; Peroxidation; Reactive oxygen species; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbadis.2024.167576
Trends Immunol. 2024 Nov 20. pii: S1471-4906(24)00272-2. [Epub ahead of print]

Nanotube-mediated mitochondrial transfer: power to the T cells!

Cosima T Baldari.

The success of T cell-based immunotherapies is limited by exhaustion, which is associated with mitochondrial dysfunction. Baldwin and colleagues show that bone marrow stromal cells (BMSCs) use nanotubes to transfer mitochondria to T cells, which increases mitochondria mass and fitness and boosts antitumor efficacy. The results pave the way to organelle-based therapies against cancer.

DOI: https://doi.org/10.1016/j.it.2024.11.001