bims-mecami 2023-12-03 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–12–03
nine papers selected by
Oltea Sampetrean, Keio University

Reprogramming endothelial cells to empower cancer immunotherapy.
The immunometabolic ecosystem in cancer.
Editorial: Therapy resistance in tumor microenvironment: metabolic reprogramming and purinergic signaling.
A PD-L1-targeting Regulator for Metabolic Reprogramming to Enhance Glutamine Inhibition-mediated Synergistic Antitumor Metabolic And Immune Therapy.
Clinically impactful metabolic subtypes of pancreatic ductal adenocarcinoma (PDAC).
Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
Targeting the lactic acid metabolic pathway for antitumor therapy.
Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.
One mutation to rule them all: Mutant KRAS controls tumor intrinsic and microenvironment signaling.

Trends Mol Med. 2023 Nov 30. pii: S1471-4914(23)00265-4. [Epub ahead of print]

Reprogramming endothelial cells to empower cancer immunotherapy.

Abigail H Cleveland, Yi Fan.

  Cancer immunity is subject to spatiotemporal regulation by leukocyte interaction with the tumor microenvironment. Growing evidence suggests an emerging role for the vasculature in tumor immune evasion and immunotherapy resistance. Beyond the conventional functions of the tumor vasculature, such as providing oxygen and nutrients to support tumor progression, we propose multiplex mechanisms for vascular regulation of tumor immunity: The immunosuppressive vascular niche locoregionally educates circulation-derived immune cells by angiocrines, aberrant endothelial metabolism induces T cell exclusion and inactivation, and topologically and biochemically abnormal vascularity forms a pathophysiological barrier that hampers lymphocyte infiltration. We postulate that genetic and metabolic reprogramming of endothelial cells may rewire the immunosuppressive vascular microenvironment to overcome immunotherapy resistance, serving as a next-generation vascular targeting strategy for cancer treatment.

Keywords:  CAR T cells; angiogenesis; cancer immunotherapy; endothelial cell metabolism; tumor microenvironment; vascular reprogramming

DOI:  https://doi.org/10.1016/j.molmed.2023.11.002
Nat Immunol. 2023 Dec;24(12): 2008-2020

The immunometabolic ecosystem in cancer.

Glenn R Bantug, Christoph Hess.

Our increased understanding of how key metabolic pathways are activated and regulated in malignant cells has identified metabolic vulnerabilities of cancers. Translating this insight to the clinics, however, has proved challenging. Roadblocks limiting efficacy of drugs targeting cancer metabolism may lie in the nature of the metabolic ecosystem of tumors. The exchange of metabolites and growth factors between cancer cells and nonmalignant tumor-resident cells is essential for tumor growth and evolution, as well as the development of an immunosuppressive microenvironment. In this Review, we will examine the metabolic interplay between tumor-resident cells and how targeted inhibition of specific metabolic enzymes in malignant cells could elicit pro-tumorigenic effects in non-transformed tumor-resident cells and inhibit the function of tumor-specific T cells. To improve the efficacy of metabolism-targeted anticancer strategies, a holistic approach that considers the effect of metabolic inhibitors on major tumor-resident cell populations is needed.

DOI: https://doi.org/10.1038/s41590-023-01675-y
Front Oncol. 2023 ;13 1297152

Editorial: Therapy resistance in tumor microenvironment: metabolic reprogramming and purinergic signaling.

Michele Zanoni, Henrique Borges da Silva, Elena Adinolfi.



Keywords:  cancer; metabolism; metastasis; purinergic signaling; resistance to therapy; stemness; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2023.1297152
Adv Mater. 2023 Nov 28. e2309094

A PD-L1-targeting Regulator for Metabolic Reprogramming to Enhance Glutamine Inhibition-mediated Synergistic Antitumor Metabolic And Immune Therapy.

Xiao-Kang Jin, Shi-Man Zhang, Jun-Long Liang, Shun-Kang Zhang, You-Teng Qin, Qian-Xiao Huang, Chuan-Jun Liu, Xian-Zheng Zhang.

  Inhibition of glutamine metabolism in tumor cells can cause metabolic compensation-mediated glycolysis enhancement and PD-L1 upregulation-induced immune evasion, significantly limiting the therapeutic efficacy of glutamine inhibitors. Here, inspired by the specific binding of receptor and ligand, a PD-L1-targeting metabolism and immune regulator (PMIR) was constructed by decorating the glutaminase inhibitor (BPTES)-loading zeolitic imidazolate framework (ZIF) with PD-L1-targeting peptides for regulating the metabolism within the tumor microenvironment (TME) to improve immunotherapy. At tumor sites, PMIR inhibited glutamine metabolism of tumor cells for elevating glutamine levels within the TME to improve the function of immune cells. Ingeniously, the accompanying PD-L1 upregulation on tumor cells caused self-amplifying accumulation of PMIR through PD-L1 targeting, while also blocking PD-L1, which had the effects of converting enemies into friends. Meanwhile, PMIR exactly offset the compensatory glycolysis, while disrupting the redox homeostasis in tumor cells via the cooperation of components of the ZIF and BPTES. These together caused immunogenic cell death of tumor cells and relieved PD-L1-mediated immune evasion, further reshaping the immunosuppressive TME and evoking robust immune responses to effectively suppress bilateral tumor progression and metastasis. This work proposed a rational strategy to surmount the obstacles in glutamine inhibition for boosting existing clinical treatments. This article is protected by copyright. All rights reserved.

Keywords:  Drug delivering; Glutamine inhibition; Metabolic reprogramming; Self-amplifying PD-L1 targeting; Tumor immunotherapy

DOI:  https://doi.org/10.1002/adma.202309094
Front Genet. 2023 ;14 1282824

Clinically impactful metabolic subtypes of pancreatic ductal adenocarcinoma (PDAC).

Jannat Pervin, Mohammad Asad, Shaolong Cao, Gun Ho Jang, Nikta Feizi, Benjamin Haibe-Kains, Joanna M Karasinska, Grainne M O'Kane, Steven Gallinger, David F Schaeffer, Daniel J Renouf, George Zogopoulos, Oliver F Bathe.

  Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a diverse tumor microenvironment. The heterogeneous cellular composition of PDAC makes it challenging to study molecular features of tumor cells using extracts from bulk tumor. The metabolic features in tumor cells from clinical samples are poorly understood, and their impact on clinical outcomes are unknown. Our objective was to identify the metabolic features in the tumor compartment that are most clinically impactful. Methods: A computational deconvolution approach using the DeMixT algorithm was applied to bulk RNASeq data from The Cancer Genome Atlas to determine the proportion of each gene's expression that was attributable to the tumor compartment. A machine learning algorithm designed to identify features most closely associated with survival outcomes was used to identify the most clinically impactful metabolic genes. Results: Two metabolic subtypes (M1 and M2) were identified, based on the pattern of expression of the 26 most important metabolic genes. The M2 phenotype had a significantly worse survival, which was replicated in three external PDAC cohorts. This PDAC subtype was characterized by net glycogen catabolism, accelerated glycolysis, and increased proliferation and cellular migration. Single cell data demonstrated substantial intercellular heterogeneity in the metabolic features that typified this aggressive phenotype. Conclusion: By focusing on features within the tumor compartment, two novel and clinically impactful metabolic subtypes of PDAC were identified. Our study emphasizes the challenges of defining tumor phenotypes in the face of the significant intratumoral heterogeneity that typifies PDAC. Further studies are required to understand the microenvironmental factors that drive the appearance of the metabolic features characteristic of the aggressive M2 PDAC phenotype.

Keywords:  deconvolution; metabolism; pancreatic cancer; pancreatic ductal adenocarcinoma; prognosis

DOI:  https://doi.org/10.3389/fgene.2023.1282824
bioRxiv. 2023 Nov 16. pii: 2023.11.14.567048. [Epub ahead of print]

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sadie Johnson, Mary McGraw, Matthew M Grabowski, Tianyao Lu, Lutz Freytag, Vinod Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin D Lathia.

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.

DOI: https://doi.org/10.1101/2023.11.14.567048
Mol Ther Oncolytics. 2023 Dec 19. 31 100740

Targeting the lactic acid metabolic pathway for antitumor therapy.

Zhi Li, Jiuwei Cui.

  Lactic acid is one of the most abundant products of cellular metabolism and has historically been considered a cell-damaging metabolic product. However, as research has deepened, the beneficial effects of lactic acid on tumor cells and the tumor microenvironment have received increasing attention from the oncology community. Lactic acid can not only provide tumor cells with energy but also act as a messenger molecule that promotes tumor growth and progression and protects tumor cells from immune cells and killing by radiation and chemotherapy. Thus, the inhibition of tumor cell lactic acid metabolism has emerged as a novel antitumor treatment strategy that can also effectively enhance the efficacy of conventional antitumor therapies. In this review, we classify the currently available therapies targeting lactic acid metabolism and examine their prospects for clinical application.

Keywords:  acidic tumor microenvironment; cancer; drug delivery; lactic acid metabolism; targeted therapy

DOI:  https://doi.org/10.1016/j.omto.2023.100740
bioRxiv. 2023 Nov 13. pii: 2023.11.08.566310. [Epub ahead of print]

Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.

Daniel Maxim Iascone, Xue Zhang, Patricia Bafford, Clementina Mesaros, Yogev Sela, Samuel Hofbauer, Shirley L Zhang, Kieona Cook, Pavel Pivarshev, Ben Z Stanger, Stewart Anderson, Chi V Dang, Amita Sehgal.

Crosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in an in vitro mouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

DOI: https://doi.org/10.1101/2023.11.08.566310
Cancer Res. 2023 Nov 28.

One mutation to rule them all: Mutant KRAS controls tumor intrinsic and microenvironment signaling.

Sören Müller, Akshay T Krishnamurty.

In a recent study published in Cancer Discovery, Hsu and colleagues employ an elegant combination of single-cell and bulk RNA-seq experiments from mouse and human colorectal cancer (CRC) samples, patient-derived organoids, 2D in vitro systems, and in vivo validation in genetically engineered CRC mouse models to investigate how mutant KRAS (KRAS*) impacts the tumor microenvironment. They identify a molecular signaling cascade downstream of KRAS* that activates a specific program of lipid-rich CAFs, promoting tumor angiogenesis and progression. These findings may lead to new therapeutic strategies for CRC patients with KRAS*.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3682