bims-mecami 2024-08-11 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–08–11
ten papers selected by
Oltea Sampetrean, Keio University

Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.
The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.
Intratumoral Microbiome: Foe or Friend in Reshaping the Tumor Microenvironment Landscape?
Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.
Cancer-associated adipocytes in the ovarian cancer microenvironment.
Aspartate in tumor microenvironment and beyond: Metabolic interactions and therapeutic perspectives.
Glutamine withdrawal leads to the preferential activation of lipid metabolism in metastatic colorectal cancer.
Phosphodiesterase-5 inhibition collaborates with vaccine-based immunotherapy to reprogram myeloid cells in pancreatic ductal adenocarcinoma.
Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer.
Targeting fatty acid oxidation enhances response to HER2-targeted therapy.

Front Immunol. 2024 ;15 1353787

Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.

Andrea Nicolini, Paola Ferrari.

  Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.

Keywords:  colorectal cancer; immunotherapy; metabolic reprogramming; tumor immune escape; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1353787
Immunity. 2024 Aug 02. pii: S1074-7613(24)00352-2. [Epub ahead of print]

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.

Christopher M Jackson, Ayush Pant, Wikum Dinalankara, John Choi, Aanchal Jain, Ryan Nitta, Eli Yazigi, Laura Saleh, Liang Zhao, Thomas R Nirschl, Christina M Kochel, Brandon Hwa-Lin Bergsneider, Denis Routkevitch, Kisha Patel, Kwang Bog Cho, Stephany Tzeng, Sarah Y Neshat, Young-Hoon Kim, Barbara J Smith, Maria Cecilia Ramello, Elena Sotillo, Xinnan Wang, Jordan J Green, Chetan Bettegowda, Gordon Li, Henry Brem, Crystal L Mackall, Drew M Pardoll, Charles G Drake, Luigi Marchionni, Michael Lim.

  Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

Keywords:  CD8(+) T cell hypofunction; Meteorin-like protein; T cell exhaustion; anti-tumor immunity; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.immuni.2024.07.003
Cells. 2024 Jul 30. pii: 1279. [Epub ahead of print]13(15):

Intratumoral Microbiome: Foe or Friend in Reshaping the Tumor Microenvironment Landscape?

Athina A Kyriazi, Makrina Karaglani, Sofia Agelaki, Stavroula Baritaki.

  The role of the microbiome in cancer and its crosstalk with the tumor microenvironment (TME) has been extensively studied and characterized. An emerging field in the cancer microbiome research is the concept of the intratumoral microbiome, which refers to the microbiome residing within the tumor. This microbiome primarily originates from the local microbiome of the tumor-bearing tissue or from translocating microbiome from distant sites, such as the gut. Despite the increasing number of studies on intratumoral microbiome, it remains unclear whether it is a driver or a bystander of oncogenesis and tumor progression. This review aims to elucidate the intricate role of the intratumoral microbiome in tumor development by exploring its effects on reshaping the multileveled ecosystem in which tumors thrive, the TME. To dissect the complexity and the multitude of layers within the TME, we distinguish six specialized tumor microenvironments, namely, the immune, metabolic, hypoxic, acidic, mechanical and innervated microenvironments. Accordingly, we attempt to decipher the effects of the intratumoral microbiome on each specialized microenvironment and ultimately decode its tumor-promoting or tumor-suppressive impact. Additionally, we portray the intratumoral microbiome as an orchestrator in the tumor milieu, fine-tuning the responses in distinct, specialized microenvironments and remodeling the TME in a multileveled and multifaceted manner.

Keywords:  cancer; immune cells; metabolism; microbiome; therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/cells13151279
Am J Physiol Cell Physiol. 2024 Aug 05.

Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.

Michala G Rolver, Marc Severin, Stine F Pedersen.

  The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increases susceptibility to oxidative stress, lipotoxicity and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions as well as of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells.

Keywords:  ferroptosis; lipid metabolism; mitochondria; oxidative phosphorylation; peroxisomes

DOI:  https://doi.org/10.1152/ajpcell.00429.2024
Am J Cancer Res. 2024 ;14(7): 3259-3279

Cancer-associated adipocytes in the ovarian cancer microenvironment.

Qiuling Cai, Jing Yang, Huiling Shen, Wenlin Xu.

  The tumor microenvironment (TME) plays a critical role in high energy metabolism during tumorigenesis, progression and metastasis. Among them, adipocytes, as an important component of the TME, can transform into cancer-associated adipocytes (CAAs) through dedifferentiation via interactions with tumor cells. These CAAs provide nutrients, growth factors, cytokines and metabolites to the tumor and later transdifferentiate into other stromal cells at a later stage to alter tumor growth, metastasis and the drug response and ultimately influence the treatment and prognosis of ovarian cancer. This review outlines the physiological functions of CAAs and discusses the progress in the use of CAAs as therapeutic targets in ovarian cancer.

Keywords:  Adipocytes; adipokines; cancer-associated adipocytes; ovarian cancer; treatment of ovarian cancer

DOI:  https://doi.org/10.62347/XZRI9189
Biochim Biophys Acta Mol Basis Dis. 2024 Aug 05. pii: S0925-4439(24)00444-7. [Epub ahead of print]1870(8): 167451

Aspartate in tumor microenvironment and beyond: Metabolic interactions and therapeutic perspectives.

Julian Wong Soon, Maria Antonietta Manca, Agnieszka Laskowska, Julia Starkova, Katerina Rohlenova, Jakub Rohlena.

  Aspartate is a proteinogenic non-essential amino acid with several essential functions in proliferating cells. It is mostly produced in a cell autonomous manner from oxalacetate via glutamate oxalacetate transaminases 1 or 2 (GOT1 or GOT2), but in some cases it can also be salvaged from the microenvironment via transporters such as SLC1A3 or by macropinocytosis. In this review we provide an overview of biosynthetic pathways that produce aspartate endogenously during proliferation. We discuss conditions that favor aspartate uptake as well as possible sources of exogenous aspartate in the microenvironment of tumors and bone marrow, where most available data have been generated. We highlight metabolic fates of aspartate, its various functions, and possible approaches to target aspartate metabolism for cancer therapy.

Keywords:  Amino acid; Biosynthesis; Cancer; Leukemia; Malate-aspartate shuttle; Respiratory chain; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbadis.2024.167451
Transl Oncol. 2024 Aug 06. pii: S1936-5233(24)00205-5. [Epub ahead of print]48 102078

Glutamine withdrawal leads to the preferential activation of lipid metabolism in metastatic colorectal cancer.

Aliye Ezgi Güleç Taşkıran, Diren Arda Karaoğlu, Cemil Can Eylem, Çağdaş Ermiş, İsmail Güderer, Emirhan Nemutlu, Seçil Demirkol Canlı, Sreeparna Banerjee.

   INTRODUCTION: Glutamine is a non-essential amino acid that is critical for cell growth. However, the differential metabolism of l-glutamine in metastatic versus primary colorectal cancer (CRC) has not been evaluated adequately.
MATERIALS AND METHODS: Differential expression of glutamine-related genes was determined in primary versus metastatic CRC. Univariate Cox regression and hierarchical clustering were used to generate a gene signature for prognostication. Untargeted metabolomics and 18O based fluxomics were used to identify differential metabolite levels and energy turnover in the paired primary (SW480) and metastatic (SW620) CRC cells. Western blot and qRT-PCR were used to validate differential gene expression. Subcellular localization of E-cadherin was determined by immunocytochemistry. Lipid droplets were visualized with Nile Red.
RESULTS: The GO term "Glutamine metabolism" was significantly enriched in metastatic versus primary tumors. Supporting this, SW620 cells showed decreased membrane localization of E-cadherin and increased motility upon l-Glutamine withdrawal. A glutamine related signature associated with worse prognosis was identified and validated in multiple datasets. A fluxomics assay revealed a slower TCA cycle in SW480 and SW620 cells upon l-Glutamine withdrawal. SW620 cells, however, could maintain high ATP levels. Untargeted metabolomics indicated the preferential metabolism of fatty acids in SW620 but not SW480 cells. Lipids were mainly obtained from the environment rather than by de novo synthesis.
CONCLUSIONS: Metastatic CRC cells can display aberrant glutamine metabolism. We show for the first time that upon l-glutamine withdrawal, SW620 (but not SW480) cells were metabolically plastic and could metabolize lipids for survival and cellular motility.

Keywords:  Colorectal cancer; L-Glutamine; Lipid metabolism; Metabolic plasticity

DOI:  https://doi.org/10.1016/j.tranon.2024.102078
JCI Insight. 2024 Aug 06. pii: e179292. [Epub ahead of print]

Phosphodiesterase-5 inhibition collaborates with vaccine-based immunotherapy to reprogram myeloid cells in pancreatic ductal adenocarcinoma.

Nicole E Gross, Zhehao Zhang, Jacob T Mitchell, Soren Charmsaz, Alexei G Hernandez, Erin M Coyne, Sarah M Shin, Diana Carolina Vargas Carvajal, Dimitrios N Sidiropoulos, Yeonju Cho, Guanglan Mo, Xuan Yuan, Courtney Cannon, Jayalaxmi Suresh Babu, Melissa R Lyman, Todd Armstrong, Luciane T Kagohara, Katherine M Bever, Dung T Le, Elizabeth M Jaffee, Elana J Fertig, Won Jin Ho.

  Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to immunotherapy. Although immune recognition can be enhanced with immunomodulatory agents including checkpoint inhibitors and vaccines, few patients experience clinical efficacy because the tumor immune microenvironment (TiME) is dominated by immunosuppressive myeloid cells that impose T cell inhibition. Inhibition of phosphodiesterase-5 (PDE5) was reported to downregulate metabolic regulators arginase and iNOS in immunosuppressive myeloid cells and enhance immunity against immune-sensitive tumors including head and neck cancers. We show for the first time that combining a PDE5 inhibitor, tadalafil, with a mesothelin-specific vaccine, anti-PD1, and anti-CTLA4 yields antitumor efficacy even against immune-resistant PDAC. To determine immunologic advantages conferred by tadalafil, we profiled the TiME using mass cytometry and single-cell RNA analysis with Domino to infer intercellular signaling. Our analyses demonstrated that tadalafil reprograms myeloid cells to be less immunosuppressive. Moreover, tadalafil synergized with the vaccine, enhancing T cell activation including mesothelin-specific T cells. Tadalafil treatment was also associated with myeloid-T cell signaling axes important for antitumor responses (e.g., Cxcr3, Il12). Our study shows that PDE5 inhibition combined with vaccine-based immunotherapy promotes pro-inflammatory states of myeloid cells, activation of T cells, and enhanced myeloid-T cell crosstalk to yield antitumor efficacy against immune-resistant PDAC.

Keywords:  Cancer immunotherapy; Immunology; Immunotherapy; Oncology; Phosphodiesterases

DOI:  https://doi.org/10.1172/jci.insight.179292
Nature. 2024 Aug 07.

Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer.

Mariluz Soula, Gokhan Unlu, Rachel Welch, Aleksey Chudnovskiy, Beste Uygur, Vyom Shah, Hanan Alwaseem, Paul Bunk, Vishvak Subramanyam, Hsi-Wen Yeh, Artem Khan, Søren Heissel, Hani Goodarzi, Gabriel D Victora, Semir Beyaz, Kıvanç Birsoy.

Cancer cells frequently alter their lipids to grow and adapt to their environment1-3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.

DOI: https://doi.org/10.1038/s41586-024-07787-1
Nat Commun. 2024 Aug 03. 15(1): 6587

Targeting fatty acid oxidation enhances response to HER2-targeted therapy.

Ipshita Nandi, Linjia Ji, Harvey W Smith, Daina Avizonis, Vasilios Papavasiliou, Cynthia Lavoie, Alain Pacis, Sherif Attalla, Virginie Sanguin-Gendreau, William J Muller.

Metabolic reprogramming, a hallmark of tumorigenesis, involves alterations in glucose and fatty acid metabolism. Here, we investigate the role of Carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in long-chain fatty acid (LCFA) oxidation, in ErbB2-driven breast cancers. In ErbB2+ breast cancer models, ablation of Cpt1a delays tumor onset, growth, and metastasis. However, Cpt1a-deficient cells exhibit increased glucose dependency that enables survival and eventual tumor progression. Consequently, these cells exhibit heightened oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Inhibiting Nrf2 or silencing its expression reduces proliferation and glucose consumption in Cpt1a-deficient cells. Combining the ketogenic diet, composed of LCFAs, or an anti-ErbB2 monoclonal antibody (mAb) with Cpt1a deficiency significantly perturbs tumor growth, enhances apoptosis, and reduces lung metastasis. Using an immunocompetent model, we show that Cpt1a inhibition promotes an antitumor immune microenvironment, thereby enhancing the efficacy of anti-ErbB2 mAbs. Our findings underscore the importance of targeting fatty acid oxidation alongside HER2-targeted therapies to combat resistance in HER2+ breast cancer patients.

DOI: https://doi.org/10.1038/s41467-024-50998-3