bims-tumime 2023-09-03 papers

bims-tumime

Biomed News

on Tumor microenvironment and metabolism

Issue of 2023–09–03
ten papers selected by
Alex Muir, University of Chicago

Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.
Spotlight on GOT2 in Cancer Metabolism.
Metabolic partitioning in the brain and its hijacking by glioblastoma.
Lipid metabolic vulnerabilities of multiple myeloma.
Tumor-initiating cells establish a niche to overcome isolation stress.
Machine learning of cellular metabolic rewiring.
Formate promotes invasion and metastasis in reliance on lipid metabolism.
Measuring the Metabolic State of Tissue-Resident Macrophages via SCENITH.
Metabolic programs of T cell tissue residency empower tumour immunity.
Succinate in the tumor microenvironment affects tumor growth and modulates tumor associated macrophages.

Nat Metab. 2023 Aug 31.

Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.

Abir Mukherjee, Divya Bezwada, Francesco Greco, Malu Zandbergen, Tong Shen, Chun-Yi Chiang, Medine Tasdemir, Johannes Fahrmann, Dmitry Grapov, Michael R La Frano, Hieu S Vu, Brandon Faubert, John W Newman, Liam A McDonnell, Luigi Nezi, Oliver Fiehn, Ralph J DeBerardinis, Ernst Lengyel.

In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.

DOI: https://doi.org/10.1038/s42255-023-00879-8
Onco Targets Ther. 2023 ;16 695-702

Spotlight on GOT2 in Cancer Metabolism.

Samuel A Kerk, Javier Garcia-Bermudez, Kivanc Birsoy, Mara H Sherman, Yatrik M Shah, Costas A Lyssiotis.

  GOT2 is at the nexus of several critical metabolic pathways in homeostatic cellular and dysregulated cancer metabolism. Despite this, recent work has emphasized the remarkable plasticity of cancer cells to employ compensatory pathways when GOT2 is inhibited. Here, we review the metabolic roles of GOT2, highlighting findings in both normal and cancer cells. We emphasize how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT2 is inhibited. We close by using this framework to discuss key considerations for future investigations into cancer metabolism.

Keywords:  mitochondria; nucleotides; pancreatic cancer; redox; transaminase; tumor microenvironment

DOI:  https://doi.org/10.2147/OTT.S382161
Genes Dev. 2023 Aug 30.

Metabolic partitioning in the brain and its hijacking by glioblastoma.

Jed de Ruiter Swain, Evdokia Michalopoulou, Evan K Noch, Michael J Lukey, Linda Van Aelst.

  The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.

Keywords:  IDH mutation; brain metabolism; cancer metabolism; glioblastoma; glioma; glioma therapy; immune suppression; tumor microenvironment

DOI:  https://doi.org/10.1101/gad.350693.123
Clin Exp Med. 2023 Aug 28.

Lipid metabolic vulnerabilities of multiple myeloma.

Roberta Torcasio, Maria Eugenia Gallo Cantafio, Raissa Kaori Ikeda, Ludovica Ganino, Giuseppe Viglietto, Nicola Amodio.

  Multiple myeloma (MM) is the second most common hematological malignancy worldwide, characterized by abnormal proliferation of malignant plasma cells within a tumor-permissive bone marrow microenvironment. Metabolic dysfunctions are emerging as key determinants in the pathobiology of MM. In this review, we highlight the metabolic features of MM, showing how alterations in various lipid pathways, mainly involving fatty acids, cholesterol and sphingolipids, affect the growth, survival and drug responsiveness of MM cells, as well as their cross-talk with other cellular components of the tumor microenvironment. These findings will provide a new path to understanding the mechanisms underlying how lipid vulnerabilities may arise and affect the phenotype of malignant plasma cells, highlighting novel druggable pathways with a significant impact on the management of MM.

Keywords:  Cholesterol; Fatty acids; Lipid metabolism; Metabolic reprogramming; Multiple myeloma; Sphingolipids

DOI:  https://doi.org/10.1007/s10238-023-01174-2
Trends Cell Biol. 2023 Aug 26. pii: S0962-8924(23)00165-4. [Epub ahead of print]

Tumor-initiating cells establish a niche to overcome isolation stress.

Chengsheng Wu, Sara M Weis, David A Cheresh.

  While the tumor microenvironment is a critical contributor to cancer progression, early steps of tumor initiation and metastasis also rely on the ability of individual tumor cells to survive and thrive at locations where tumor stroma or immune infiltration has yet to be established. In this opinion article, we use the term 'isolation stress' to broadly describe the challenges that individual tumor cells must overcome during the initiation and expansion of the primary tumor beyond permissive boundaries and metastatic spread into distant sites, including a lack of cell-cell contact, adhesion to protumor extracellular matrix proteins, and access to nutrients, oxygen, and soluble factors that support growth. In particular, we highlight the ability of solitary tumor cells to autonomously generate a specialized fibronectin-enriched extracellular matrix to create their own pericellular niche that supports tumor initiation. Cancer cells that can creatively evade the effects of isolation stress not only become more broadly stress tolerant, they also tend to show enhanced stemness, drug resistance, tumor initiation, and metastasis.

Keywords:  fibronectin; integrins; isolation stress; tumor-initiating niche

DOI:  https://doi.org/10.1016/j.tcb.2023.08.001
bioRxiv. 2023 Aug 14. pii: 2023.08.11.552957. [Epub ahead of print]

Machine learning of cellular metabolic rewiring.

Joao B Xavier.

Metabolic rewiring allows cells to adapt their metabolism in response to evolving environmental conditions. Traditional metabolomics techniques, whether targeted or untargeted, often struggle to interpret these adaptive shifts. Here we introduce MetaboLiteLearner , a machine learning framework that harnesses the detailed fragmentation patterns from electron ionization (EI) collected in scan mode during gas chromatography/mass spectrometry (GC/MS) to predict abundance changes in metabolically adapted cells. When tested on breast cancer cells with different preferences to metastasize to specific organs, MetaboLiteLearner successfully predicted the impact of metabolic rewiring on metabolites withheld from the training dataset using only the EI spectra, without metabolite identification or pre-existing knowledge of metabolic networks. Our analysis highlights shared and unique metabolomic shifts between brain- and lung-homing metastatic lineages, suggesting potential organ-tailored cellular adaptations. MetaboLiteLearner 's integration of machine learning and metabolomics paves the way for new insights into complex cellular adaptations.
Significance: Metabolic rewiring-the cellular adaptation to shifts in environment and nutrients-plays key roles in many contexts, including cancer metastasis. Traditional metabolomics often falls short of capturing the nuances of these metabolic shifts. This work introduces MetaboliLiteLearner , a machine learning framework that harnesses the rich fragmentation patterns from electron ionization collected in scan mode during gas chromatography/mass spectrometry, paving the way for enhanced insights into metabolic adaptations. Demonstrating its robustness on a breast cancer model, we highlight MetaboliLiteLearner 's potential to reshape our understanding of metabolic rewiring, with implications in diagnostics, therapeutics, and basic cell biology.

DOI: https://doi.org/10.1101/2023.08.11.552957
Cell Rep. 2023 Aug 30. pii: S2211-1247(23)01045-8. [Epub ahead of print]42(9): 113034

Formate promotes invasion and metastasis in reliance on lipid metabolism.

Catherine Delbrouck, Nicole Kiweler, Oleg Chen, Vitaly I Pozdeev, Lara Haase, Laura Neises, Anaïs Oudin, Aymeric Fouquier d'Hérouël, Ruolin Shen, Lisa Schlicker, Rashi Halder, Antoine Lesur, Anne Schuster, Nadja I Lorenz, Christian Jaeger, Maureen Feucherolles, Gilles Frache, Martyna Szpakowska, Andy Chevigne, Michael W Ronellenfitsch, Etienne Moussay, Marie Piraud, Alexander Skupin, Almut Schulze, Simone P Niclou, Elisabeth Letellier, Johannes Meiser.

  Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism.

Keywords:  CP: Cancer; CP: Metabolism; cancer metastasis; formate overflow; invasion; one-carbon metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.113034
Methods Mol Biol. 2024 ;2713 363-376

Measuring the Metabolic State of Tissue-Resident Macrophages via SCENITH.

Andrea Vogel, Paulina García González, Rafael J Argüello.

  Functional reprograming of cells is linked to a process of metabolic rewiring that is adapted for such new functions or microenvironment. Macrophages are present in all tissues and exposed to different microenvironments throughout our body. Profiling energetic metabolism of tissue resident and other heterogeneous populations of macrophages in vitro and ex vivo is technologically very challenging. We have recently developed a method to functionally profile energetic metabolism with single-cell resolution, named SCENITH. This method can be performed rapidly ex vivo and does not require specialized equipment. In this book chapter, we will summarize the tissue processing, the procedure and methods, the analysis and example of results, and a series of frequently asked questions.

Keywords:  Energetic metabolism; FACS; Flow cytometry; Glycolytic capacity; Immunometabolism; Macrophages; Metabolic dependencies; Mitochondrial dependence; Protein synthesis; SCENITH; Single-cell resolution

DOI:  https://doi.org/10.1007/978-1-0716-3437-0_25
Nature. 2023 Aug 30.

Metabolic programs of T cell tissue residency empower tumour immunity.

Miguel Reina-Campos, Maximilian Heeg, Kelly Kennewick, Ian T Mathews, Giovanni Galletti, Vida Luna, Quynhanh Nguyen, Hongling Huang, J Justin Milner, Kenneth H Hu, Amy Vichaidit, Natalie Santillano, Brigid S Boland, John T Chang, Mohit Jain, Sonia Sharma, Matthew F Krummel, Hongbo Chi, Steven J Bensinger, Ananda W Goldrath.

Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.

DOI: https://doi.org/10.1038/s41586-023-06483-w
Biomaterials. 2023 Aug 26. pii: S0142-9612(23)00300-9. [Epub ahead of print]301 122292

Succinate in the tumor microenvironment affects tumor growth and modulates tumor associated macrophages.

Sahil Inamdar, Abhirami P Suresh, Joslyn L Mangal, Nathan D Ng, Alison Sundem, Hoda Shokrollahzadeh Behbahani, Thomas E Rubino, Jordan R Yaron, Taravat Khodaei, Matthew Green, Marion Curtis, Abhinav P Acharya.

  Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene succinate (PES) microparticles (MPs) biomaterial mediated controlled delivery of succinate in the TME modulates macrophage responses. Administering PES MPs locally with or without a BRAF inhibitor systemically in an immune-defective aging mice with clinically relevant BRAFV600E mutated YUMM1.1 melanoma decreased tumor volume three-fold. PES MPs in the TME also led to maintenance of M1 macrophages with up-regulation of TSLP and type 1 interferon pathway. Impressively, this led to generation of pro-inflammatory adaptive immune responses in the form of increased T helper type 1 and T helper type 17 cells in the TME. Overall, our findings from this challenging tumor model suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.

Keywords:  Cancer; Immunometabolism; Macrophages; Melanoma; Succinate

DOI:  https://doi.org/10.1016/j.biomaterials.2023.122292