bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2023‒09‒24
twelve papers selected by
Alex Muir, University of Chicago

  1. Biochim Biophys Acta Rev Cancer. 2023 Sep 16. pii: S0304-419X(23)00133-6. [Epub ahead of print] 188984
      Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism is often considered as the digestion and absorption process of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.
    Keywords:  Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment
  2. Cancer Discov. 2023 Sep 20.
      The tumor microenvironment (TME) restricts anti-tumor CD8+ T cell function and immunotherapy responses. Cancer cells compromise metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate one carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T cell fitness and anti-tumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for the enhanced tumor control. Our data demonstrate formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T cell function.
  3. Biochim Biophys Acta Rev Cancer. 2023 Sep 15. pii: S0304-419X(23)00136-1. [Epub ahead of print] 188987
      Citrate is a key metabolite of the Krebs cycle that can also be exported in the cytosol, where it performs several functions. In normal cells, citrate sustains protein acetylation, lipid synthesis, gluconeogenesis, insulin secretion, bone tissues formation, spermatozoid mobility, and immune response. Dysregulation of citrate metabolism is implicated in several pathologies, including cancer. Here we discuss how cancer cells use citrate to sustain their proliferation, survival, and metastatic progression. Also, we propose two paradoxically opposite strategies to reduce tumour growth by targeting citrate metabolism in preclinical models. In the first strategy, we propose to administer in the tumor microenvironment a high amount of citrate, which can then act as a glycolysis inhibitor and apoptosis inducer, whereas the other strategy targets citrate transporters to starve cancer cells from citrate. These strategies, effective in several preclinical in vitro and in vivo cancer models, could be exploited in clinics, particularly to increase sensibility to current anti-cancer agents.
    Keywords:  Cancer; Citrate; Drug resistance; Warburg effect; pmCiC
  4. Cell Chem Biol. 2023 Sep 21. pii: S2451-9456(23)00284-2. [Epub ahead of print]30(9): 1012-1014
      Metabolic competition within the tumor microenvironment (TME) shapes the efficacy of anticancer immunity. In the August 3rd issue of Nature, Guo et al.1 show that glutamine is an intercellular metabolic checkpoint between cancer and immune cells. Targeting glutamine metabolism in the TME is a promising strategy to improve anti-cancer therapy.
  5. Nat Cancer. 2023 Sep 18.
      Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. While the metabolic role of ACSS2 in cancer is well described, the consequences of blocking tumor acetate metabolism on the tumor microenvironment and antitumor immunity are unknown. We demonstrate that blocking ACSS2, switches cancer cells from acetate consumers to producers of acetate thereby freeing acetate for tumor-infiltrating lymphocytes to use as a fuel source. We show that acetate supplementation metabolically bolsters T-cell effector functions and proliferation. Targeting ACSS2 with CRISPR-Cas9 guides or a small-molecule inhibitor promotes an antitumor immune response and enhances the efficacy of chemotherapy in preclinical breast cancer models. We propose a paradigm for targeting acetate metabolism in cancer in which inhibition of ACSS2 dually acts to impair tumor cell metabolism and potentiate antitumor immunity.
  6. J Exp Clin Cancer Res. 2023 Sep 23. 42(1): 245
      Macrophages are highly plastic in different tissues and can differentiate into functional subpopulations under different stimuli. Tumor-associated macrophages (TAMs) are one of the most important innate immune cells implicated in the establishment of an immunosuppressive tumor microenvironment (TME). Recent evidence pinpoints the critical role of metabolic reprogramming in dictating pro-tumorigenic functions of TAMs. Both tumor cells and macrophages undergo metabolic reprogramming to meet energy demands in the TME. Understanding the metabolic rewiring in TAMs can shed light on immune escape mechanisms and provide insights into repolarizing TAMs towards anti-tumorigenic function. Here, we discuss how metabolism impinges on the functional divergence of macrophages and its relevance to macrophage polarization in the TME.
    Keywords:  Metabolic reprogramming; Polarization; Signaling pathways; TAMs; TME
  7. Cancer Immunol Immunother. 2023 Sep 21.
      Tumor-infiltrating T cells are promising drug targets to modulate the tumor microenvironment. However, tumor-infiltrating T lymphocytes, as central targets of cancer immunotherapy, show considerable heterogeneity and dynamics across tumor microenvironments and cancer types that may fundamentally influence cancer growth, metastasis, relapse, and response to clinical drugs. The T cell heterogeneity not only refers to the composition of subpopulations but also divergent metabolic states of T cells. Comparing to the diversity of tumor-infiltrating T cell compositions that have been well recognized, the metabolic diversity of T cells deserves more attention for precision immunotherapy. Single-cell sequencing technology enables panoramic stitching of the tumor bulk, partly by showing the metabolic-related gene expression profiles of tumor-infiltrating T cells at a single-cell resolution. Therefore, we here discuss T cell metabolism reprogramming triggered by tumor microenvironment as well as the potential application of metabolic targeting drugs. The tumor-infiltrating T cells metabolic pathway addictions among different cancer types are also addressed in this brief review.
    Keywords:  Cancer metabolism; Single-cell sequencing; T cell metabolism; Tumor microenvironment; Tumor-infiltrating T cell
  8. Clin Cancer Res. 2023 Sep 18.
      PURPOSE: PTEN loss-of-function/PI3K pathway hyperactivation is associated with poor therapeutic outcomes and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies in Pb-Cre;PTENfl/flTrp53fl/fl genetically engineered mice (GEM) with aggressive-variant prostate cancer (AVPC) demonstrated tumor growth control in 60% mice following androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki)/PD-1 antibody combination, via abrogating lactate cross-talk between cancer cells and tumor-associated macrophages (TAM), and suppression of histone lactylation (H3K18lac)/phagocytic activation within TAM. Here, we targeted immunometabolic mechanism(s) of PI3Ki resistance, with the goal of durable tumor control in AVPC.EXPERIMENTAL DESIGN: Pb-Cre;PTENfl/flTrp53fl/fl GEM were treated with PI3Ki (copanlisib), MEK inhibitor (trametinib) or Porcupine inhibitor (LGK`974) singly or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo co-culture mechanistic studies were performed on GEM tumors or corresponding tumor-derived cell lines.
    RESULTS: Given our proteomic profiling showing persistent MEK signaling within tumors of PI3Ki-resistant GEM, we tested whether addition of trametinib to copanlisib enhances tumor control in GEM, and observed 80% overall response rate via additive suppression of lactate within TME and H3K18lac within TAM, relative to copanlisib (37.5%) monotherapy. The 20% resistant mice demonstrated feedback Wnt/b-catenin activation, resulting in restoration of lactate secretion by tumor cells and H3K18lac within TAM. Co-targeting Wnt/b-catenin signaling with LGK'974 in combination with PI3Ki/MEKi, demonstrated durable tumor control in 100% mice via H3K18lac suppression and complete TAM activation.
    CONCLUSIONS: Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.
  9. Curr Opin Biotechnol. 2023 Sep 13. pii: S0958-1669(23)00103-9. [Epub ahead of print]84 102993
      The potential for 'anti-cancer' diets to markedly alter cancer risk and prognosis has captured the imagination of patients, physicians, and researchers alike, but many of these dietary recommendations come from correlative studies that attribute certain diets to altered cancer risk. While provocative, little is known about the molecular mechanisms behind how these dietary interventions impact cancer progression. Within this context, however, changes in tumor lipid metabolism are emerging as a key contributor. In this review, we examine the current understanding of lipid metabolism in the tumor microenvironment (TME), suggesting how diet-induced changes in lipid composition may regulate tumor progression and therapeutic efficacy. By dissecting various cellular pathways involved in lipid metabolism, we highlight how diet modulates the balance between saturated and unsaturated fatty acid (FA) species in tumors to impact cancer cell and stromal cell function. Finally, we describe how current cancer therapies may synergize with diet to improve therapeutic efficacy.
  10. Cancer Res. 2023 Sep 22.
      Excessive fructose intake is associated with the occurrence, progression, and poor prognosis of various tumors. A better understanding of the mechanisms underlying the functions of fructose in cancer could facilitate the development of better treatment and prevention strategies. In this study, we investigated the functional association between fructose utilization and pancreatic ductal adenocarcinoma (PDAC) progression. Fructose could be taken up and metabolized by PDAC cells and provided an adaptive survival mechanism for PDAC cells under glucose deficient conditions. GLUT5-mediated fructose metabolism maintained the survival, proliferation, and invasion capacities of PDAC cells in vivo and in vitro. Fructose metabolism not only provided ATP and biomass to PDAC cells but also conferred metabolic plasticity to the cells, making them more adaptable to the tumor microenvironment. Mechanistically, fructose activated AMPK-mTORC1 signaling pathway to inhibit glucose deficiency-induced autophagic cell death. Moreover, the fructose specific transporter GLUT5 was highly expressed in PDAC tissues and was an independent marker of disease progression in PDAC patients. These findings provide mechanistic insights into the role of fructose in promoting PDAC progression and offer potential strategies for targeting metabolism to treat PDAC.
  11. JCI Insight. 2023 Sep 21. pii: e163022. [Epub ahead of print]
      Glycolysis is highly enhanced in Pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for PDAC patients, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides new insights into crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.
    Keywords:  Cancer; Metabolism; Oncology