bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–04–23
ten papers selected by
Oltea Sampetrean, Keio University
  1. Learning the metabolic language of cancer.
  2. Impact of context-dependent autophagy states on tumor progression.
  3. Extracellular Domains of CAR Reprogram T-Cell Metabolism Without Antigen Stimulation.
  4. Glucose metabolism of TAMs in tumor chemoresistance and metastasis.
  5. The metabolic cross-talk between cancer and T cells.
  6. The role of lipid metabolic reprogramming in tumor microenvironment.
  7. A core-satellite micellar system against primary tumors and their lymphatic metastasis through modulation of fatty acid metabolism blockade and tumor-associated macrophages.
  8. Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.
  9. The role of lipid metabolism in cancer radioresistance.
  10. Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells.
  1. Nature. 2023 Apr;616(7958): 670-671
    Learning the metabolic language of cancer.
    Minervo Perez, Jordan L Meier.
      
    Keywords:  Cancer; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-01024-x
  2. Nat Cancer. 2023 Apr 17.
    Impact of context-dependent autophagy states on tumor progression.
    Mohamad Assi, Alec C Kimmelman.
      Macroautophagy is a cellular quality-control process that degrades proteins, protein aggregates and damaged organelles. Autophagy plays a fundamental role in cancer where, in the presence of stressors (for example, nutrient starvation, hypoxia, mechanical pressure), tumor cells activate it to degrade intracellular substrates and provide energy. Cell-autonomous autophagy in tumor cells and cell-nonautonomous autophagy in the tumor microenvironment and in the host converge on mechanisms that modulate metabolic fitness, DNA integrity and immune escape and, consequently, support tumor growth. In this Review, we will discuss insights into the tumor-modulating roles of autophagy in different contexts and reflect on how future studies using physiological culture systems may help to understand the complexity and open new therapeutic avenues.
    DOI:  https://doi.org/10.1038/s43018-023-00546-7
  3. bioRxiv. 2023 Apr 04. pii: 2023.04.03.533021. [Epub ahead of print]
    Extracellular Domains of CAR Reprogram T-Cell Metabolism Without Antigen Stimulation.
    Aliya Lakhani, Ximin Chen, Laurence C Chen, Mobina Khericha, Yvonne Y Chen, Junyoung O Park.
      Metabolism is an indispensable part of T-cell proliferation, activation, and exhaustion, yet the metabolism of chimeric antigen receptor (CAR)-T cells remains incompletely understood. CARs are comprised of extracellular domains that determine cancer specificity, often using single-chain variable fragments (scFvs), and intracellular domains that trigger signaling upon antigen binding. Here we show that CARs differing only in the scFv reprogram T-cell metabolism differently. Even in the absence of antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observe basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harboring rituximab scFv, unlike other similar anti-CD20 scFvs. Disparate rituximab and 14g2a-based anti-GD2 CAR-T cells are similarly hypermetabolic and channel excess nutrients to nitrogen overflow metabolism. Since CAR-dependent metabolic reprogramming alters cellular energetics, nutrient utilization, and proliferation, metabolic profiling should be an integral part of CAR-T cell development.
    DOI:  https://doi.org/10.1101/2023.04.03.533021
  4. Trends Cell Biol. 2023 Apr 18. pii: S0962-8924(23)00049-1. [Epub ahead of print]
    Glucose metabolism of TAMs in tumor chemoresistance and metastasis.
    Juan Liu, Xuetao Cao.
      Tumor-associated macrophages (TAMs) are critical in promoting tumor progression and therapeutic resistance. In adapting to metabolic changes in the tumor microenvironment (TME), TAMs reprogram their metabolisms and acquire immunosuppressive and pro-tumor properties. Increased glucose metabolism in TAMs leads to the accumulation of a variety of oncometabolites that exhibit potent tumor-promoting capacity via regulating gene expression and signaling transduction. Glucose uptake also fuels O-GlcNAcylation and other post-translational modifications to promote pro-tumor polarization and function of TAMs. Glucose metabolism coordinates interactions between TAMs and various types of cells in the TME, creating a complex network that facilitates tumor progression. Targeting glucose metabolism represents a promising strategy to switch TAMs from pro-tumor toward anti-tumor function for cancer therapy.
    Keywords:  O-GlcNAcylation; glucose metabolism; lactic acids; tumor metastasis; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.008
  5. Trends Biochem Sci. 2023 Apr 18. pii: S0968-0004(23)00080-4. [Epub ahead of print]
    The metabolic cross-talk between cancer and T cells.
    Silvia Cadenas-De Miguel, Giulia Lucianer, Ilaria Elia.
      The metabolic cross-talk between cancer cells and T cells dictates cancer formation and progression. These cells possess metabolic plasticity. Thus, they adapt their metabolic profile to meet their phenotypic requirements. However, the nutrient microenvironment of a tumor is a very hostile niche in which these cells are forced to compete for the available nutrients. The hyperactive metabolism of tumor cells often outcompetes the antitumorigenic CD8+ T cells while promoting the protumorigenic exhausted CD8+ T cells and T regulatory (Treg) cells. Thus, cancer cells elude the immune response and spread in an uncontrolled manner. Identifying the metabolic pathways necessary to shift the balance from a protumorigenic to an antitumorigenic immune phenotype is essential to potentiate antitumor immunity.
    Keywords:  antitumorigenic T cells; immunometabolism; protumorigenic T cells; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tibs.2023.03.004
  6. Theranostics. 2023 ;13(6): 1774-1808
    The role of lipid metabolic reprogramming in tumor microenvironment.
    Kai Yang, Xiaokun Wang, Chenghu Song, Zhao He, Ruixin Wang, Yongrui Xu, Guanyu Jiang, Yuan Wan, Jie Mei, Wenjun Mao.
      Metabolic reprogramming is one of the most important hallmarks of malignant tumors. Specifically, lipid metabolic reprogramming has marked impacts on cancer progression and therapeutic response by remodeling the tumor microenvironment (TME). In the past few decades, immunotherapy has revolutionized the treatment landscape for advanced cancers. Lipid metabolic reprogramming plays pivotal role in regulating the immune microenvironment and response to cancer immunotherapy. Here, we systematically reviewed the characteristics, mechanism, and role of lipid metabolic reprogramming in tumor and immune cells in the TME, appraised the effects of various cell death modes (specifically ferroptosis) on lipid metabolism, and summarized the antitumor therapies targeting lipid metabolism. Overall, lipid metabolic reprogramming has profound effects on cancer immunotherapy by regulating the immune microenvironment; therefore, targeting lipid metabolic reprogramming may lead to the development of innovative clinical applications including sensitizing immunotherapy.
    Keywords:  immunotherapy; lipid metabolic reprogramming; therapeutic target; tumor microenvironment
    DOI:  https://doi.org/10.7150/thno.82920
  7. Nanoscale. 2023 Apr 21.
    A core-satellite micellar system against primary tumors and their lymphatic metastasis through modulation of fatty acid metabolism blockade and tumor-associated macrophages.
    Xuan He, Tao Deng, Jiaxin Li, Rong Guo, Yashi Wang, Ting Li, Shuya Zang, Jiaxin Li, Ling Zhang, Man Li, Qin He.
      Lymph nodes (LNs) are the initial sanctuary of various metastatic tumor cells, and thus a precise lymphatic drug delivery strategy is necessary for the effective inhibition of metastasis. However, the complex biological barriers have restrained the drug delivery to tumor-draining lymph nodes (TDLNs). Metastatic tumor cells would undergo metabolic adaptation towards fatty acid oxidation (FAO) upon reaching the lipid-rich LNs. Herein, to inhibit primary tumors and their lymphatic metastasis, a core-satellite matrix metalloproteinase 2 (MMP-2) responsive micellar system was developed for sequential delivery of paclitaxel (PTX) and the metabolism-regulating drug etomoxir (ET) to tumors and TDLNs, respectively. Upon arrival at the tumor microenvironment (TME), the small satellite micelle encapsulating ET was detached from the core micelle in response to MMP-2, which not only drained to TDLNs via tumor-draining lymphatic vessels and inhibited the FAO of metastatic tumor cells, but also blocked M2-like macrophage polarization in the TME. Meanwhile, the core micelle containing PTX could largely accumulate in the TME and kill tumor cells. In an orthotopic 4T1 breast cancer model, the tumor and TDLN dual-targeted core-satellite micellar system effectively inhibited the growth of the primary tumor and alleviated immune suppression by blocking macrophage polarization. More importantly, tumor lymphatic metastasis was suppressed through FAO metabolic regulation. This strategy provides a promising approach for TDLN targeted therapy against breast cancer and its lymphatic metastasis.
    DOI:  https://doi.org/10.1039/d2nr04693h
  8. Cancer Drug Resist. 2023 ;6(1): 138-150
    Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.
    Yoko Tabe, Marina Konopleva.
      In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment, acute myeloid leukemia (AML) cells continuously adjust their metabolic state. To meet the biochemical demands of their increased proliferation, AML cells strongly depend on mitochondrial oxidative phosphorylation (OXPHOS). Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation (FAO), which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance. For targeting these metabolic vulnerabilities of AML cells, inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential. Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells, enabling them to acquire resistance against OXPHOS and FAO inhibitors. These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors. Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.
    Keywords:  Bone marrow microenvironment; acute myeloid leukemia; energy metabolism; fatty acid oxidation; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.20517/cdr.2022.133
  9. Clin Transl Oncol. 2023 Apr 20.
    The role of lipid metabolism in cancer radioresistance.
    Dandan An, Danyi Zhai, Chao Wan, Kunyu Yang.
      Radiotherapy is one of the main therapies for cancer. The process leading to radioresistance is still not fully understood. Cancer radiosensitivity is related to the DNA reparation of cancer cells and the tumor microenvironment (TME), which supports cancer cell survival. Factors that affect DNA reparation and the TME can directly or indirectly affect the radiosensitivity of cancer. Recent studies have shown that lipid metabolism in cancer cells, which is involved in the stability of cell membrane structure, energy supply and signal transduction of cancer cells, can also affect the phenotype and function of immune cells and stromal cells in the TME. In this review, we discussed the effects of lipid metabolism on the radiobiological characteristics of cancer cells and the TME. We also summarized recent advances in targeted lipid metabolism as a radiosensitizer and discussed how these scientific findings could be translated into clinical practice to improve the radiosensitivity of cancer.
    Keywords:  Cancer; Cholesterol; Fatty acid oxidation; Lipid metabolism; Radioresistance; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12094-023-03134-4
  10. Dev Cell. 2023 Apr 17. pii: S1534-5807(23)00148-X. [Epub ahead of print]
    Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells.
    Valeria Amodeo, Timothy Davies, Amalia Martinez-Segura, Melanie P Clements, Holly Simpson Ragdale, Andrew Bailey, Mariana Silva Dos Santos, James I MacRae, Joao Mokochinski, Holger Kramer, Claudia Garcia-Diaz, Alex P Gould, Samuel Marguerat, Simona Parrinello.
      Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear. Here, we show that p53 maintains quiescence by inducing fatty-acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPARα to upregulate FAO genes. Dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumor initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention.
    Keywords:  fatty acid oxidation; metabolism; neural stem cells; p53; quiescence; tumour initiation
    DOI:  https://doi.org/10.1016/j.devcel.2023.03.021
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