bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2023‒10‒01
thirteen papers selected by
Alex Muir, University of Chicago

  1. Trends Pharmacol Sci. 2023 Sep 26. pii: S0165-6147(23)00179-7. [Epub ahead of print]
      The adaptation of natural killer (NK) cells to conditions in the microenvironment of tumors is deeply affected by their metabolic activity, itself a result of nutrient availability and the metabolism of the cancer cells themselves. Elevated rates of glycolysis and lipid metabolism in cancers not only lead to the accumulation of immunosuppressive byproducts but also contribute to an environment of elevated concentrations of extracellular metabolites. This results in altered NK cell bioenergetics through changes in transcriptional and translational profiles, ultimately affecting their pharmacology and impairing NK cell responses. However, understanding the metabolic processes that drive alterations in immunological signaling on NK cells remains both difficult and vastly underexplored. We discuss the varied and complex drivers of NK cell metabolism in homeostasis and the tumor microenvironment (TME), challenges associated with their targetability, and unexplored therapeutic opportunities.
    Keywords:  NK cells; cancer immunotherapy; cancer metabolism; immunometabolism; tumor bioenergetics
  2. bioRxiv. 2023 Sep 17. pii: 2023.09.15.557984. [Epub ahead of print]
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality and limited efficacious therapeutic options. PDAC cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. One critical metabolic shift in PDAC cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PK). Pancreatic cancer cells preferentially upregulate pyruvate kinase muscle isoform 2 isoform (PKM2). PKM2 expression reprograms many metabolic pathways, but little is known about its impact on cystine metabolism. Cystine metabolism is critical for supporting survival through its role in defense against ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by unchecked lipid peroxidation. To improve our understanding of the role of PKM2 in cystine metabolism and ferroptosis in PDAC, we generated PKM2 knockout (KO) human PDAC cells. Fascinatingly, PKM2KO cells demonstrate a remarkable resistance to cystine starvation mediated ferroptosis. This resistance to ferroptosis is caused by decreased PK activity, rather than an isoform-specific effect. We further utilized stable isotope tracing to evaluate the impact of glucose and glutamine reprogramming in PKM2KO cells. PKM2KO cells depend on glutamine metabolism to support antioxidant defenses against lipid peroxidation, primarily by increased glutamine flux through the malate aspartate shuttle and utilization of ME1 to produce NADPH. Ferroptosis can be synergistically induced by the combination of PKM2 activation and inhibition of the cystine/glutamate antiporter in vitro . Proof-of-concept in vivo experiments demonstrate the efficacy of this mechanism as a novel treatment strategy for PDAC.Highlights: PKM2KO in pancreatic ductal adenocarcinoma (PDAC) cells produces enhanced defense against cystine starvation induced ferroptosis.Pharmacologic activation of pyruvate kinase (PK) activity promotes ferroptosis under cystine starvation, while inhibition promotes ferroptosis survival in PDAC cells.Decrease in PK activity reprograms glutamine metabolism to increase use of malic enzyme 1 and promote survival under cystine starvation in PDAC cells. Cystine starvation and activation of pyruvate kinase synergistically decreases progression of pancreatic cancer in vivo .
  3. Genes (Basel). 2023 Sep 19. pii: 1818. [Epub ahead of print]14(9):
      Previous studies have shown that inhibition of TNF family member FN14 (gene: TNFRSF12A) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that TNFRSF12A expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted TNFRSF12A induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the Tnfrsf12a promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of Tnfrsf12a and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model. These findings highlight a connection between metabolic stress and cancer cachexia development.
    Keywords:  FN14; TNFRSF12A; alpha-ketoglutarate; cachexia; cancer; colon cancer; histone
  4. bioRxiv. 2023 Sep 15. pii: 2023.09.15.557892. [Epub ahead of print]
      The tumor microenvironment (TME) is characterized by a network of cancer cells, recruited immune cells and extracellular matrix (ECM) in a hypoxic micro-environment. However, the specific role of neutrophils in the TME, and their interactions with other immune cells is still not well understood. Thus, there is a need to investigate the interaction of primary neutrophils with tumor cells and the resulting effects on tumor development. Here we use both standard well plate culture and an under oil microfluidic (UOM) assay with an integrated extracellular cell matrix (ECM) bridge to elucidate how naive primary neutrophils respond to both patient derived tumor cells and tumor cell lines. Our data demonstrated that both patient derived HNSCC tumor cells and MDA-MB-231 breast cancer cells trigger cluster formation in neutrophils, and the swarm of neutrophils restricts tumor invasion through the generation of reactive oxygen species (ROS) and neutrophil extracellular trap (NETs) release within the swarm. However, we also observed that the presence of neutrophils downregulates granzyme B in NK-92 cells and the resulting NETs can obstruct NK cells from penetrating the tumor mass in vitro suggesting a dual role for neutrophils in the TME. Further, using label-free optical metabolic imaging (OMI) we observed changes in the metabolic activities of primary neutrophils during the different swarming phases when challenged with tumor cells. Finally, our data demonstrates that neutrophils in direct contact, or in close proximity, with tumor cells exhibit greater metabolic activities (lower nicotinamide adenine dinucleotide phosphate (NAD(P)H) mean lifetime) compared to non-contact neutrophils.
  5. Front Oncol. 2023 ;13 1235711
      T cells are an important component of adaptive immunity and T-cell-derived lymphomas are very complex due to many functional sub-types and functional elasticity of T-cells. As with other tumors, tissues specific factors are crucial in the development of T-cell lymphomas. In addition to neoplastic cells, T- cell lymphomas consist of a tumor micro-environment composed of normal cells and stroma. Numerous studies established the qualitative and quantitative differences between the tumor microenvironment and normal cell surroundings. Interaction between the various component of the tumor microenvironment is crucial since tumor cells can change the microenvironment and vice versa. In normal T-cell development, T-cells must respond to various stimulants deferentially and during these courses of adaptation. T-cells undergo various metabolic alterations. From the stage of quiescence to attention of fully active form T-cells undergoes various stage in terms of metabolic activity. Predominantly quiescent T-cells have ATP-generating metabolism while during the proliferative stage, their metabolism tilted towards the growth-promoting pathways. In addition to this, a functionally different subset of T-cells requires to activate the different metabolic pathways, and consequently, this regulation of the metabolic pathway control activation and function of T-cells. So, it is obvious that dynamic, and well-regulated metabolic pathways are important for the normal functioning of T-cells and their interaction with the microenvironment. There are various cell signaling mechanisms of metabolism are involved in this regulation and more and more studies have suggested the involvement of additional signaling in the development of the overall metabolic phenotype of T cells. These important signaling mediators include cytokines and hormones. The impact and role of these mediators especially the cytokines on the interplay between T-cell metabolism and the interaction of T-cells with their micro-environments in the context of T-cells lymphomas are discussed in this review article.
    Keywords:  T cell lymphoma; cell signaling; cytokine; metabolism; tumor micro environment
  6. Cell Rep. 2023 Sep 26. pii: S2211-1247(23)01187-7. [Epub ahead of print]42(10): 113175
      The mechanical properties of solid tumors influence tumor cell phenotype and the ability to invade surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state, which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peritumoral brain tissues, but tumor stiffness is heterogeneous where tumor edges are softer than the tumor core. We then developed 3D scaffolds with μ-compressive moduli resembling either stiffer tumor core or softer peritumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis, which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells.
    Keywords:  CP: Cancer; CP: Metabolism; extracellular matrix; tissue mechanics
  7. bioRxiv. 2023 Sep 17. pii: 2023.09.14.557797. [Epub ahead of print]
      Three-dimensional (3D) in vitro models are essential in cancer research, but they often neglect physical forces. In our study, we combined patient-derived tumor organoids with a microfluidic organ-on-chip system to investigate colorectal cancer (CRC) invasion in the tumor microenvironment (TME). This allowed us to create patient-specific tumor models and assess the impact of physical forces on cancer biology. Our findings showed that the organoid-on-chip models more closely resembled patient tumors at the transcriptional level, surpassing organoids alone. Using 'omics' methods and live-cell imaging, we observed heightened responsiveness of KRAS mutant tumors to TME mechanical forces. These tumors also utilized the γ-aminobutyric acid (GABA) neurotransmitter as an energy source, increasing their invasiveness. This bioengineered model holds promise for advancing our understanding of cancer progression and improving CRC treatments.Highlights: Microfluidic organ-on-chip system integrated with patient-derived CRC organoidsPhysical forces influence invasion, particularly in KRAS mutant tumor cellsGABAergic signaling contributes to increased invasion within a dynamic TMEThis model explores patient heterogeneity, TME interactions, and cancer progression.
  8. bioRxiv. 2023 Sep 17. pii: 2023.09.15.557802. [Epub ahead of print]
      In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy.
  9. Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Sep 23. pii: S1388-1981(23)00122-1. [Epub ahead of print] 159398
      Hypoxia plays an important role in pancreatic cancer progression. It drives various metabolic reprogramming in cells including that of lipids, which in turn, can modify the structure and function of cell membranes. Homeostatic adaptation of membranes is well-recognized, but how and if it is regulated in hypoxic pancreatic cancer and its relation to aggressive phenotype and metastasis remains elusive. Here we show hypoxia-induced extensive global lipid remodelling spanning changes in lipid classes, unsaturation levels, glyceryl backbone and acyl chain lengths. No major modulation of plasma membrane biophysical properties revealed a decoupling of lipidome modulation from membrane properties under hypoxia. This was supported by observing minor changes in the lipidome of plasma membranes under hypoxia. Further, hypoxia increased migration and invasion underpinned by reduced actin volume, cell cortical stiffness and facile tether dynamics. In conclusion, we demonstrate buffering of the lipidome alterations leading to a homeostatic membrane response. These findings will help to understand the hypoxic regulation of pancreatic membrane homeostasis and identify tangible theranostic avenues.
    Keywords:  Cell membranes; Hypoxia; Lipidomics; Membrane biophysics; Pancreatic cancer
  10. Int J Mol Sci. 2023 Sep 21. pii: 14403. [Epub ahead of print]24(18):
      Malignant melanoma is a very aggressive skin cancer, characterized by a heterogeneous nature and high metastatic potential. The incidence of melanoma is continuously increasing worldwide, and it is one of the most common cancers in young adults. In the past twenty years, our understanding of melanoma biology has increased profoundly, and disease management for patients with disseminated disease has improved due to the emergence of immunotherapy and targeted therapy. However, a significant fraction of patients relapse or do not respond adequately to treatment. This can partly be explained by the complex signaling between the tumor and its microenvironment, giving rise to melanoma phenotypes with different patterns of disease progression. This review focuses on the key aspects and complex relationship between pathogenesis, genetic abnormalities, tumor microenvironment, cellular plasticity, and metabolic reprogramming in melanoma. By acquiring a deeper understanding of the multifaceted features of melanomagenesis, we can reach a point of more individualized and patient-centered disease management and reduced costs of ineffective treatments.
    Keywords:  cellular plasticity; malignant melanoma; metabolic reprogramming; molecular classifications; mutational burden; phenotype switching; treatment resistance; tumor microenvironment
  11. Clin Transl Oncol. 2023 Sep 23.
      Tumor cells must resist the host's immune system while maintaining growth under harsh conditions of acidity and hypoxia, which indicates that tumors are more robust than normal tissue. Immunotherapeutic agents have little effect on solid tumors, mostly because of the tumor density and the difficulty of penetrating deeply into the tissue to achieve the theoretical therapeutic effect. Various therapeutic strategies targeting the tumor microenvironment (TME) have been developed. Immunometabolic disorders play a dominant role in treatment resistance at both the TME and host levels. Understanding immunometabolic factors and their treatment potential may be a way forward for tumor immunotherapy. Here, we summarize the metabolism of substances that affect tumor progression, the crosstalk between the TME and immunosuppression, and some potential tumor-site targets. We also summarize the progress and challenges of tumor immunotherapy.
    Keywords:  Immunotherapy; Metabolic crosstalk; Tumor inflammation; Tumor metabolism; Tumor microenvironment
  12. Cancer Discov. 2023 Sep 28.
      Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* suppresses anti-tumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAFs) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) which upregulates the expression of the pro-adipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce vascular endothelial growth factor A (VEGFA) to spur angiogenesis. In KRAS*-driven CRC mouse models, genetic or pharmacological neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human CRC, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven CRC.