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Metabolic reprogramming in the tumor microenvironment of liver cancer.

ABSTRACT: The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains durable clinical remission following immunotherapy. In this review, we elucidate the metabolic communication between liver cancer cells and their surrounding immune cells and discuss how metabolic reprogramming of liver cancer impacts the immune microenvironment and the efficacy of anticancer immunotherapy. We also describe the crucial role of the gut-liver axis in remodeling the metabolic crosstalk of immune surveillance and escape, highlighting novel therapeutic opportunities.

SUBMITTER: Lin J

PROVIDER: S-EPMC10832230 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Metabolic reprogramming in the tumor microenvironment of liver cancer.

Lin Jian J Rao Dongning D Zhang Mao M Gao Qiang Q

Journal of hematology & oncology 20240131 1

The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains dur ...[more]

PMID: 38297372

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Project description:BackgroundHistidine metabolism is crucial in role in tumor biology, contributing to tumor progression, immune regulation, and metabolic reprogramming. In hepatocellular carcinoma (HCC), dysregulated histidine metabolism may promote tumor growth and immune evasion, although the specific mechanisms remain poorly understood.MethodsUsing single-cell RNA sequencing, the expression patterns of histidine metabolism-related genes were evaluated across different cell types in HCC samples. In vivo and in vitro experiments were conducted to validate how histidine treatment affects macrophage and T-cell function. Furthermore, the TCGA database was utilized to construct a prognostic model to identify the key gene BUD23 and to examine its correlation with metabolism and immune infiltration.ResultsThe proportion of parenchymal cells exhibiting high histidine metabolism was significantly increased, accompanied by a general reduction in immune and stromal cell infiltration. Notably, macrophages and T cells demonstrated impaired antitumor functions. In the high histidine metabolism group, multiple critical cell communication pathways (e.g., MIF, CLEC, MHC II) were downregulated, macrophages shifted toward immunosuppressive subpopulations, T cells exhibited an exhaustion phenotype, and CD8 + T-cell activation was diminished. Further in vivo and in vitro co-culture experiments confirmed that elevated histidine concentrations promoted M2 polarization in macrophages and weakened T-cell cytotoxicity, accelerating tumor proliferation. According to TCGA analyses, BUD23 was upregulated in the high histidine metabolism group and significantly negatively correlated with patient survival and immune cell infiltration. Silencing BUD23 boosted immune cell activation and cytotoxic effects, effectively reversing the immunosuppressive microenvironment. A multivariable Cox regression-based prognostic model indicated unfavorable outcomes in patients with high histidine metabolism.ConclusionHistidine metabolism drives tumor cell metabolic reprogramming and reshapes the tumor immune microenvironment through intercellular communication, thereby promoting tumor progression. BUD23 shows promise as a biomarker for prognosis and immune response prediction in liver cancer. This study provides new therapeutic targets and theoretical support for liver cancer treatment by targeting histidine metabolism.

Project description:The tumor microenvironment (TME) plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Thus, better insight into tumor-host interactions is required. Most of these processes involve the metabolic reprogramming of cells. Here, we focused on this reprogramming in cancerous cells and its effect on the TME. A major limitation in the study of tumor-host interactions is the difficulty in separating cancerous from non-cancerous signaling pathways within a tumor. Our strategy involved specifically silencing the expression of VDAC1 in the mitochondria of human-derived A549 lung cancer xenografts in mice, but not in the mouse-derived cells of the TME. Next-generation sequencing (NGS) analysis allows distinguishing the human or mouse origin of genes, thus enabling the separation of the bidirectional cross-talk between the TME and malignant cells. We demonstrate that depleting VDAC1 in cancer cells led to metabolic reprogramming, tumor regression, and the disruption of tumor-host interactions. This was reflected in the altered expression of a battery of genes associated with TME, including those involved in extracellular matrix organization and structure, matrix-related peptidases, angiogenesis, intercellular interacting proteins, integrins, and growth factors associated with stromal activities. We show that metabolic rewiring upon mitochondrial VDAC1 silencing in cancer cells affected several components of the TME, such as structural protein matrix metalloproteinases and Lox, and elicited a stromal response resembling the reaction to a foreign body in wound healing. As tumor progression requires a cooperative interplay between the host and cancer cells, and the ECM is intensively remodeled during cancer progression, VDAC1 depletion induced metabolic reprogramming that targeted both tumor cells and resulted in the alteration of the whole spectrum of TME-related genes, affecting the reciprocal feedback between ECM molecules, host cells, and cancer cells. Thus, VDAC1 depletion using si-VDAC1 represents therapeutic potential, inhibiting cancer cell proliferation and also inducing the modulation of TME components, which influences cancer progression, migration, and invasion.

Project description:Background: The leading cause of poor prognosis in colorectal cancer (CRC) is the presence of colorectal cancer-initiating cells (CCICs). The interplay between the tumor microenvironment (TME) and CRC cells induces reacquisition of initiating cell characteristics, but the underlying mechanisms remain elusive. Methods: Candidate molecules were screened by global differential cDNA expression profiles of CCICs, which were enriched from patient-derived tumor xenograft models. Luciferase reporters and chromatin immunoprecipitation assays were used to explore the mechanism of TME factors regulating the transcription of ANKRD22. The effects of Ankyrin repeat domain-containing protein 22 (ANKRD22) on energy metabolism were monitored by extracellular flux and 13C-based metabolic flux analysis. Mass spectrometry was used to identify the interacting partners of ANKRD22. Morphological changes of CCICs overexpressing ANKRD22 were observed by electron microscopy. The effects of ANKRD22 on mitochondrial lipid metabolism were analyzed by lipidomics. Results: We identified a novel nucleus-encoded mitochondrial membrane protein, ANKRD22, which was upregulated in CCICs. We found that ANKRD22 was induced by the p38/MAX pathway activated by different TME stimuli. As a key transcription factor, MAX promoted the transcription of ANKRD22. Expression of ANKRD22 promoted glycolysis associated with a decrease in ATP/ADP and an increase in AMP/ATP levels, which were related to its interaction with pyruvate dehydrogenase kinase isoform 1 (PDK1) and multiple subunits of ATP synthase. Further, in CCICs, ANKRD22 cooperated with the lipid transport protein, Extended Synaptotagmin-1 (E-Syt1), to transport excess lipids into mitochondria and reduced the number of mitochondria in an autophagy-independent manner, thus meeting the metabolic requirements of CCICs. Conclusion: ANKRD22 induced by TME promotes the metabolic reprogramming of CRC cells. Our study has identified ANKRD22/E-Syt1 as a potential target for eradicating CCICs.

Dataset Information

Metabolic reprogramming in the tumor microenvironment of liver cancer.

Publications

Metabolic reprogramming in the tumor microenvironment of liver cancer.

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