bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2023–10–29
thirteen papers selected by
Alex Muir, University of Chicago
  1. Proline metabolism shapes the tumor microenvironment: from collagen deposition to immune evasion.
  2. Molecular Mechanisms Underpinning Immunometabolic Reprogramming: How the Wind Changes during Cancer Progression.
  3. The Significance of Microenvironmental and Circulating Lactate in Breast Cancer.
  4. LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.
  5. How protons pave the way to aggressive cancers.
  6. The immunometabolic landscape of bone marrow cells in multiple sclerosis.
  7. Innate lymphoid cells and tumor-derived lactic acid: novel contenders in an enduring game.
  8. ASCT2 is the primary serine transporter in cancer cells.
  9. Stronger Together: Cancer Clones Cooperate to Alleviate Growth Barriers in Critical Cancer Progression Transitions.
  10. Tumoral Lactobacillus iners Induces Therapy Resistance Through Metabolic Rewiring.
  11. CD36 Protects Tumor Cells from Lipotoxicity During Metastasis.
  12. The glucose transporter 2 regulates CD8+ T cell function via environment sensing.
  13. Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma.
  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. FASEB J. 2023 11;37(11): e23267
    The immunometabolic landscape of bone marrow cells in multiple sclerosis.
    Yutong Shi, Caiyun Qi, Ying Bai.
      In multiple sclerosis (MS), the bone marrow hematopoietic system supplies immune cells to orchestrate central nervous system (CNS) inflammation and autoimmunity. Understanding the metabolic processes within the bone marrow is essential for unraveling the phenotype and function of immune cells. However, a comprehensive exploration of the metabolic landscape and its association with systemic immune response in MS at the single-cell level has yet to be elucidated. Herein, we conducted an analysis of 70 289 bone marrow cells obtained from seven patients with MS and seven health controls (referenced as HRA001783) to address this question. Our focus was primarily on investigating the metabolic preferences of diverse immune cell populations and delineating their metabolic manifestations in the bone marrow microenvironment of MS. Through our analysis, we observed the activation of carbohydrate and amino acid metabolic pathways in the bone marrow cells of MS patients. Notably, we discovered significant metabolic alterations in cell-cell communication within the plasma cell population in the MS bone marrow. These findings shed light on the complex metabolic landscape within the bone marrow niche during MS and highlight the distinctive metabolic characteristics of plasma cells in this context, which may provoke novel understanding of MS pathogenesis and promote future design of immune therapies.
    Keywords:  bone marrow; metabolism; multiple sclerosis; single-cell sequencing
    DOI:  https://doi.org/10.1096/fj.202300694R
  7. Front Immunol. 2023 ;14 1236301
    Innate lymphoid cells and tumor-derived lactic acid: novel contenders in an enduring game.
    Mateusz Marciniak, Marek Wagner.
      Aerobic glycolysis, also known as the Warburg effect, has for a prolonged period of time been perceived as a defining feature of tumor metabolism. The redirection of glucose utilization towards increased production of lactate by cancer cells enables their rapid proliferation, unceasing growth, and longevity. At the same time, it serves as a significant contributor to acidification of the tumor microenvironment, which, in turn, imposes substantial constraints on infiltrating immune cells. Here, we delve into the influence of tumor-derived lactic acid on innate lymphoid cells (ILCs) and discuss potential therapeutic approaches. Given the abundance of ILCs in barrier tissues such as the skin, we provide insights aimed at translating this knowledge into therapies that may specifically target skin cancer.
    Keywords:  innate lymphoid cells; lactate; lactic acid; melanoma; metabolism; skin; skin cancer
    DOI:  https://doi.org/10.3389/fimmu.2023.1236301
  8. bioRxiv. 2023 Oct 11. pii: 2023.10.09.561530. [Epub ahead of print]
    ASCT2 is the primary serine transporter in cancer cells.
    Kelly O Conger, Christopher Chidley, Mete Emir Ozgurses, Huiping Zhao, Yumi Kim, Svetlana E Semina, Philippa Burns, Vipin Rawat, Ryan Sheldon, Issam Ben-Sahra, Jonna Frasor, Peter K Sorger, Gina M DeNicola, Jonathan L Coloff.
      The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo , others are auxotrophic for serine and therefore reliant on the uptake of exogenous serine. Importantly, however, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (coded for by the gene SLC1A5 ) as the primary serine transporter in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target in serine metabolism.
    DOI:  https://doi.org/10.1101/2023.10.09.561530
  9. Cancer Res. 2023 Oct 23.
    Stronger Together: Cancer Clones Cooperate to Alleviate Growth Barriers in Critical Cancer Progression Transitions.
    Zachary T Compton, Diego Mallo, Carlo C Maley.
      Hershey and colleagues recently showed how clones in a triple-negative breast cancer cell line cooperate for their mutual fitness benefit. In this system, clones exchange soluble metabolites to increase their in vitro growth rate at low population densities, therefore mitigating the documented growth barrier that reduces individual fitness in small tumor cell populations (Allee effect). Such cooperation could aid important transitions in cancer progression in which cancer cell populations are small, like invasion or metastasis. Using orthotopic transplantation, the authors demonstrate that this cooperation is functional in one such transition in vivo, increasing the metastatic load and number of metastases, which are usually polyclonal. Together, these findings highlight the need to consider ecological interactions to properly understand tumor growth dynamics, and how they complement the standing evolutionary model of cancer progression in our quest to understand and treat cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3255
  10. 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
  11. Cancer Discov. 2023 Oct 27. OF1
    CD36 Protects Tumor Cells from Lipotoxicity During Metastasis.
      CD36 supports metastasis by regulating lipid homeostasis during matrix detachment in breast cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-173
  12. Nat Metab. 2023 Oct 26.
    The glucose transporter 2 regulates CD8+ T cell function via environment sensing.
    Hongmei Fu, Juho Vuononvirta, Silvia Fanti, Fabrizia Bonacina, Antonio D'Amati, Guosu Wang, Thanushiyan Poobalasingam, Maria Fankhaenel, Davide Lucchesi, Rachel Coleby, David Tarussio, Bernard Thorens, Robert J Hearnden, M Paula Longhi, Paul Grevitt, Madeeha H Sheikh, Egle Solito, Susana A Godinho, Michele Bombardieri, David M Smith, Dianne Cooper, Asif J Iqbal, Jeffrey C Rathmell, Samuel Schaefer, Valle Morales, Katiuscia Bianchi, Giuseppe Danilo Norata, Federica M Marelli-Berg.
      T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation.
    DOI:  https://doi.org/10.1038/s42255-023-00913-9
  13. Sci Adv. 2023 Oct 27. 9(43): eadf1332
    Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma.
    Brett W Stringer, Manam Inushi De Silva, Zarina Greenberg, Alejandra Noreña Puerta, Robert Adams, Bridget Milky, Michael Zabolocki, Mark van den Hurk, Lisa M Ebert, Christine Fairly Bishop, Simon J Conn, Ganessan Kichenadasse, Michael Z Michael, Rebecca J Ormsby, Santosh Poonoose, Cedric Bardy.
      Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
    DOI:  https://doi.org/10.1126/sciadv.adf1332
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