bims-mecami 2023-06-25 papers

Issue of 2023–06–25
six papers selected by
Oltea Sampetrean, Keio University

J Immunol. 2023 Jun 21. pii: ji2200715. [Epub ahead of print]

Differential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells.

Matthew Z Madden, Xiang Ye, Channing Chi, Emilie L Fisher, Melissa M Wolf, Gabriel A Needle, Jackie E Bader, Andrew R Patterson, Bradley I Reinfeld, Madelyn D Landis, Emma S Hathaway, Jason E Muka, Richard T O'Neil, John Karijolich, Mary Philip, Jeffrey C Rathmell.

Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-l-norleucine (DON), or by glutamine-depleted conditions (No Q) produce distinct metabolic differentiation trajectories in murine CD8 T cells. T cell activation with CB-839 treatment had a milder effect than did DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, whereas DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of persisting cells in adoptive transfer studies, but those T cells that remained could expand normally upon secondary Ag encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with reduced persistence, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.

DOI: https://doi.org/10.4049/jimmunol.2200715

Nat Commun. 2023 Jun 22. 14(1): 3724

Hypoxia induced responses are reflected in the stromal proteome of breast cancer.

Silje Kjølle, Kenneth Finne, Even Birkeland, Vandana Ardawatia, Ingeborg Winge, Sura Aziz, Gøril Knutsvik, Elisabeth Wik, Joao A Paulo, Heidrun Vethe, Dimitrios Kleftogiannis, Lars A Akslen.

Cancers are often associated with hypoxia and metabolic reprogramming, resulting in enhanced tumor progression. Here, we aim to study breast cancer hypoxia responses, focusing on secreted proteins from low-grade (luminal-like) and high-grade (basal-like) cell lines before and after hypoxia. We examine the overlap between proteomics data from secretome analysis and laser microdissected human breast cancer stroma, and we identify a 33-protein stromal-based hypoxia profile (33P) capturing differences between luminal-like and basal-like tumors. The 33P signature is associated with metabolic differences and other adaptations following hypoxia. We observe that mRNA values for 33P predict patient survival independently of molecular subtypes and basic prognostic factors, also among low-grade luminal-like tumors. We find a significant prognostic interaction between 33P and radiation therapy.

DOI: https://doi.org/10.1038/s41467-023-39287-7

Br J Cancer. 2023 Jun 21.

Rethinking our approach to cancer metabolism to deliver patient benefit.

Saverio Tardito, Craig MacKay.

Altered cellular metabolism is a major mechanism by which tumours support nutrient consumption associated with increased cellular proliferation. Selective dependency on specific metabolic pathways provides a therapeutic vulnerability that can be targeted in cancer therapy. Anti-metabolites have been used clinically since the 1940s and several agents targeting nucleotide metabolism are now well established as standard of care treatment in a range of indications. However, despite great progress in our understanding of the metabolic requirements of cancer and non-cancer cells within the tumour microenvironment, there has been limited clinical success for novel agents targeting pathways outside of nucleotide metabolism. We believe that there is significant therapeutic potential in targeting metabolic processes within cancer that is yet to be fully realised. However, current approaches to identify novel targets, test novel therapies and select patient populations most likely to benefit are sub-optimal. We highlight recent advances in technologies and understanding that will support the identification and validation of novel targets, re-evaluation of existing targets and design of optimal clinical positioning strategies to deliver patient benefit.

DOI: https://doi.org/10.1038/s41416-023-02324-9

Nat Metab. 2023 Jun 19.

A multimodal atlas of tumour metabolism reveals the architecture of gene-metabolite covariation.

Elisa Benedetti, Eric Minwei Liu, Cerise Tang, Fengshen Kuo, Mustafa Buyukozkan, Tricia Park, Jinsung Park, Fabian Correa, A Ari Hakimi, Andrew M Intlekofer, Jan Krumsiek, Ed Reznik.

Tumour metabolism is controlled by coordinated changes in metabolite abundance and gene expression, but simultaneous quantification of metabolites and transcripts in primary tissue is rare. To overcome this limitation and to study gene-metabolite covariation in cancer, we assemble the Cancer Atlas of Metabolic Profiles of metabolomic and transcriptomic data from 988 tumour and control specimens spanning 11 cancer types in published and newly generated datasets. Meta-analysis of the Cancer Atlas of Metabolic Profiles reveals two classes of gene-metabolite covariation that transcend cancer types. The first corresponds to gene-metabolite pairs engaged in direct enzyme-substrate interactions, identifying putative genes controlling metabolite pool sizes. A second class of gene-metabolite covariation represents a small number of hub metabolites, including quinolinate and nicotinamide adenine dinucleotide, which correlate to many genes specifically expressed in immune cell populations. These results provide evidence that gene-metabolite covariation in cellularly heterogeneous tissue arises, in part, from both mechanistic interactions between genes and metabolites, and from remodelling of the bulk metabolome in specific immune microenvironments.

DOI: https://doi.org/10.1038/s42255-023-00817-8

World J Stem Cells. 2023 May 26. 15(5): 281-301

How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells.

María Belén Novoa Díaz, Pedro Carriere, Claudia Gentili.

Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.

Keywords: Cancer progression; Colorectal cancer; Colorectal cancer stem cells; Gut microbiota; Tumor microenvironment factors; Tumor stroma

DOI: https://doi.org/10.4252/wjsc.v15.i5.281

Commun Biol. 2023 Jun 20. 6(1): 653

Blood-brain barrier disruption defines the extracellular metabolome of live human high-grade gliomas.

The extracellular microenvironment modulates glioma behaviour. It remains unknown if blood-brain barrier disruption merely reflects or functionally supports glioma aggressiveness. We utilised intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions of gliomas and evaluated the global extracellular metabolome via ultra-performance liquid chromatography tandem mass spectrometry. Among 162 named metabolites, guanidinoacetate (GAA) was 126.32x higher in enhancing tumour than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumour than brain. With exception of GAA, and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumour and brain microdialysate were modest and less consistent. The enhancing, but not the non-enhancing glioma metabolome, was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies will determine how the altered extracellular metabolome impacts glioma behaviour.

DOI: https://doi.org/10.1038/s42003-023-05035-2