bims-mecami 2023-10-29 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–10–29
eleven papers selected by
Oltea Sampetrean, Keio University

Molecular Mechanisms Underpinning Immunometabolic Reprogramming: How the Wind Changes during Cancer Progression.
Proline metabolism shapes the tumor microenvironment: from collagen deposition to immune evasion.
Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity.
Tumoral Lactobacillus iners Induces Therapy Resistance Through Metabolic Rewiring.
LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.
MCT4 blockade increases the efficacy of immune checkpoint blockade.
How protons pave the way to aggressive cancers.
The Significance of Microenvironmental and Circulating Lactate in Breast Cancer.
Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.
Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.
Acidosis promotes the metastatic colonization of lung cancer via remodeling of the extracellular matrix and vasculogenic mimicry.

Genes (Basel). 2023 Oct 17. pii: 1953. [Epub ahead of print]14(10):

Molecular Mechanisms Underpinning Immunometabolic Reprogramming: How the Wind Changes during Cancer Progression.

Irene Flati, Mauro Di Vito Nolfi, Francesca Dall'Aglio, Davide Vecchiotti, Daniela Verzella, Edoardo Alesse, Daria Capece, Francesca Zazzeroni.

  Metabolism and the immunological state are intimately intertwined, as defense responses are bioenergetically expensive. Metabolic homeostasis is a key requirement for the proper function of immune cell subsets, and the perturbation of the immune-metabolic balance is a recurrent event in many human diseases, including cancer, due to nutrient fluctuation, hypoxia and additional metabolic changes occurring in the tumor microenvironment (TME). Although much remains to be understood in the field of immunometabolism, here, we report the current knowledge on both physiological and cancer-associated metabolic profiles of immune cells, and the main molecular circuits involved in their regulation, highlighting similarities and differences, and emphasizing immune metabolic liabilities that could be exploited in cancer therapy to overcome immune resistance.

Keywords:  AMPK; NF-κB; PI3K/Akt/mTOR; cancer; immunometabolism; immunosuppressive TME

DOI:  https://doi.org/10.3390/genes14101953
Curr Opin Biotechnol. 2023 Oct 19. pii: S0958-1669(23)00121-0. [Epub ahead of print]84 103011

Proline metabolism shapes the tumor microenvironment: from collagen deposition to immune evasion.

Emily J Kay, Sara Zanivan, Alessandro Rufini.

Proline is a nonessential amino acid, and its metabolism has been implicated in numerous malignancies. Together with a direct role in regulating cancer cells' proliferation and survival, proline metabolism plays active roles in shaping the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) display high rates of proline biosynthesis to support the production of collagen for the extracellular matrix (ECM). Indeed, impaired proline metabolism in CAFs results in reduced collagen deposition and compromises the growth and metastatic spread of cancer. Moreover, the rate of proline metabolism regulates intracellular reactive oxygen species (ROS) levels, which influence the production and release of cytokines from cancer cells, contributing toward an immune-permissive TME. Hence, targeting proline metabolism is a promising anticancer strategy that could improve patients' outcome and response to immunotherapy.

DOI: https://doi.org/10.1016/j.copbio.2023.103011
bioRxiv. 2023 Oct 03. pii: 2023.10.02.560316. [Epub ahead of print]

Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity.

Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.

Targeting of specific metabolic pathways in tumor cells has the potential to sensitize them to immune-mediated attack. Here we provide evidence for a specific means of mitochondrial respiratory Complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of the CI subunits Ndufs4 and Ndufs6 , but not other subunits, induces an immune-dependent tumor growth attenuation in mouse melanoma models. We show that deletion of Ndufs4 induces expression of the transcription factor Nlrc5 and genes in the MHC class I antigen presentation and processing pathway. This induction of MHC-related genes is driven by an accumulation of pyruvate dehydrogenase-dependent mitochondrial acetyl-CoA downstream of CI subunit deletion. This work provides a novel functional modality by which selective CI inhibition restricts tumor growth, suggesting that specific targeting of Ndufs4 , or related CI subunits, increases T-cell mediated immunity and sensitivity to ICB.

DOI: https://doi.org/10.1101/2023.10.02.560316
Cancer Discov. 2023 Oct 27. OF1

Tumoral Lactobacillus iners Induces Therapy Resistance Through Metabolic Rewiring.

Tumoral Lactobacillus iners predicts poor chemoradiation response and decreased survival in cervical cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-172
Res Sq. 2023 Oct 05. pii: rs.3.rs-3401154. [Epub ahead of print]

LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.

Peiwen Chen, Fatima Khan, Yiyu Lin, Heba Ali, Lizhi Pang, Madeline Dunterman, Wen-Hao Hsu, Katie Frenis, R Grant Rowe, Derek Wainwright, Kathleen McCortney, Leah Billingham, Jason Miska, Craig Horbinski, Maciej Lesniak.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase (LDH) inhibitor stiripentol (an FDA-approved anti-seizure drug for Dravet Syndrome) emerges as the top hit. Combined profiling and functional studies demonstrate that LDHA-directed ERK pathway activates YAP1/STAT3 transcriptional co-activators in glioblastoma cells to upregulate CCL2 and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.

DOI: https://doi.org/10.21203/rs.3.rs-3401154/v1
J Immunother Cancer. 2023 Oct;pii: e007349. [Epub ahead of print]11(10):

MCT4 blockade increases the efficacy of immune checkpoint blockade.

Nathalie Babl, Sonja-Maria Decking, Florian Voll, Michael Althammer, Ada Sala-Hojman, Roberta Ferretti, Clarissa Korf, Christian Schmidl, Lisa Schmidleithner, Benedikt Nerb, Carina Matos, Gudrun E Koehl, Peter Siska, Christina Bruss, Fabian Kellermeier, Katja Dettmer, Peter J Oefner, Marvin Wichland, Ines Ugele, Christopher Bohr, Wolfgang Herr, Shivapriya Ramaswamy, Timo Heinrich, Christian Herhaus, Marina Kreutz, Kathrin Renner.

   BACKGROUND & AIMS: Intratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be prognostic for the survival of patients with rectal cancer, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance.
METHODS: To determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, we examined the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor in a colorectal carcinoma (CRC) tumor spheroid model co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with an antibody against programmed cell death ligand-1(PD-L1).
RESULTS: Inhibition of MCT4 was sufficient to reduce lactate efflux in three-dimensional (3D) CRC spheroids but not in two-dimensional cell-cultures. Co-administration of the MCT4 inhibitor and ICB augmented immune cell infiltration, T-cell function and decreased CRC spheroid viability in a 3D co-culture model of human CRC spheroids with blood leukocytes. Accordingly, combination of MCT4 and ICB increased intratumoral pH, improved leukocyte infiltration and T-cell activation, delayed tumor growth, and prolonged survival in vivo. MCT1 inhibition exerted no further beneficial impact.
CONCLUSIONS: These findings demonstrate that single MCT4 inhibition represents a novel therapeutic approach to reverse lactic-acid driven immunosuppression and might be suitable to improve ICB efficacy.

Keywords:  Drug Therapy, Combination; Immune Checkpoint Inhibitors; Immunologic Surveillance; Lymphocytes, Tumor-Infiltrating; Metabolism; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2023-007349
Nat Rev Cancer. 2023 Oct 26.

How protons pave the way to aggressive cancers.

Pawel Swietach, Ebbe Boedtkjer, Stine Falsig Pedersen.

Cancers undergo sequential changes to proton (H+) concentration and sensing that are consequences of the disease and facilitate its further progression. The impact of protonation state on protein activity can arise from alterations to amino acids or their titration. Indeed, many cancer-initiating mutations influence pH balance, regulation or sensing in a manner that enables growth and invasion outside normal constraints as part of oncogenic transformation. These cancer-supporting effects become more prominent when tumours develop an acidic microenvironment owing to metabolic reprogramming and disordered perfusion. The ensuing intracellular and extracellular pH disturbances affect multiple aspects of tumour biology, ranging from proliferation to immune surveillance, and can even facilitate further mutagenesis. As a selection pressure, extracellular acidosis accelerates disease progression by favouring acid-resistant cancer cells, which are typically associated with aggressive phenotypes. Although acid-base disturbances in tumours often occur alongside hypoxia and lactate accumulation, there is now ample evidence for a distinct role of H+-operated responses in key events underpinning cancer. The breadth of these actions presents therapeutic opportunities to change the trajectory of disease.

DOI: https://doi.org/10.1038/s41568-023-00628-9
Int J Mol Sci. 2023 Oct 19. pii: 15369. [Epub ahead of print]24(20):

The Significance of Microenvironmental and Circulating Lactate in Breast Cancer.

Vincenza Frisardi, Simone Canovi, Salvatore Vaccaro, Raffaele Frazzi.

  Lactate represents the main product of pyruvate reduction catalyzed by the lactic dehydrogenase family of enzymes. Cancer cells utilize great quantities of glucose, shifting toward a glycolytic metabolism. With the contribution of tumor stromal cells and under hypoxic conditions, this leads toward the acidification of the extracellular matrix. The ability to shift between different metabolic pathways is a characteristic of breast cancer cells and is associated with an aggressive phenotype. Furthermore, the preliminary scientific evidence concerning the levels of circulating lactate in breast cancer points toward a correlation between hyperlactacidemia and poor prognosis, even though no clear linkage has been demonstrated. Overall, lactate may represent a promising metabolic target that needs to be investigated in breast cancer.

Keywords:  acidosis; aerobic glycolysis; breast cancer; lactate

DOI:  https://doi.org/10.3390/ijms242015369
Antioxidants (Basel). 2023 Sep 30. pii: 1818. [Epub ahead of print]12(10):

Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.

Nourhane Ammar, Maya Hildebrandt, Claudia Geismann, Christian Röder, Timo Gemoll, Susanne Sebens, Ania Trauzold, Heiner Schäfer.

  Metabolic compartmentalization of stroma-rich tumors, like pancreatic ductal adenocarcinoma (PDAC), greatly contributes to malignancy. This involves cancer cells importing lactate from the microenvironment (reverse Warburg cells) through monocarboxylate transporter-1 (MCT1) along with substantial phenotype alterations. Here, we report that the reverse Warburg phenotype of PDAC cells compensated for the shortage of glutamine as an essential metabolite for redox homeostasis. Thus, oxidative stress caused by glutamine depletion led to an Nrf2-dependent induction of MCT1 expression in pancreatic T3M4 and A818-6 cells. Moreover, greater MCT1 expression was detected in glutamine-scarce regions within tumor tissues from PDAC patients. MCT1-driven lactate uptake supported the neutralization of reactive oxygen species excessively produced under glutamine shortage and the resulting drop in glutathione levels that were restored by the imported lactate. Consequently, PDAC cells showed greater survival and growth under glutamine depletion when utilizing lactate through MCT1. Likewise, the glutamine uptake inhibitor V9302 and glutaminase-1 inhibitor CB839 induced oxidative stress in PDAC cells, along with cell death and cell cycle arrest that were again compensated by MCT1 upregulation and forced lactate uptake. Our findings show a novel mechanism by which PDAC cells adapt their metabolism to glutamine scarcity and by which they develop resistance against anticancer treatments based on glutamine uptake/metabolism inhibition.

Keywords:  anaplerosis; drug resistance; pancreas; tumor metabolism

DOI:  https://doi.org/10.3390/antiox12101818
Nat Commun. 2023 Oct 27. 14(1): 6858

Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.

Hao Wu, Xiufeng Zhao, Sophia M Hochrein, Miriam Eckstein, Gabriela F Gubert, Konrad Knöpper, Ana Maria Mansilla, Arman Öner, Remi Doucet-Ladevèze, Werner Schmitz, Bart Ghesquière, Sebastian Theurich, Jan Dudek, Georg Gasteiger, Alma Zernecke, Sebastian Kobold, Wolfgang Kastenmüller, Martin Vaeth.

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41467-023-42634-3
Int J Oncol. 2023 Dec;pii: 136. [Epub ahead of print]63(6):

Acidosis promotes the metastatic colonization of lung cancer via remodeling of the extracellular matrix and vasculogenic mimicry.

Wan-Yi Shie, Pin-Hsuan Chu, Mark Yen-Ping Kuo, Huei-Wen Chen, Meng-Tie Lin, Xuan-Jie Su, Yi-Ling Hong, Han-Yi Elizabeth Chou.

  Acidosis is a hallmark of the tumor microenvironment caused by the metabolic switch from glucose oxidative phosphorylation to glycolysis. It has been associated with tumor growth and progression; however, the precise mechanism governing how acidosis promotes metastatic dissemination has yet to be elucidated. In the present study, a long‑term acidosis model was established using patient‑derived lung cancer cells, to identify critical components of metastatic colonization via transcriptome profiling combined with both in vitro and in vivo functional assays, and association analysis using clinical samples. Xenograft inoculates of 1 or 10 acidotic cells mimicking circulating tumor cell clusters were shown to exhibit increased tumor incidence compared with their physiological pH counterparts. Transcriptomics revealed that profound remodeling of the extracellular matrix (ECM) occurred in the acidotic cells, including upregulation of the integrin subunit α‑4 (ITGA4) gene. In clinical lung cancer, ITGA4 expression was found to be upregulated in primary tumors with metastatic capability, and this trait was retained in the corresponding secondary tumors. Expression of ITGA4 was markedly upregulated around the vasculogenic mimicry structures of the acidotic tumors, while acidotic cells exhibited a higher ability of vasculogenic mimicry in vitro. Acidosis was also found to induce the enrichment of side population cells, suggesting an enhanced resistance to noxious attacks of the tumor microenvironment. Taken together, these results demonstrated that acidosis actively contributed to tumor metastatic colonization, and novel mechanistic insights into the therapeutic management and prognosis of lung cancer were discussed.

Keywords:  ECM; acidosis; colonization; metastasis; vasculogenic mimicry

DOI:  https://doi.org/10.3892/ijo.2023.5584