Background: Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA.
Methods: Cholangiocarcinogenesis was induced in rats (TAA) and mice (Jnk + CCl + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-KRAS cells. Cell signaling, growth, gene regulation and [U-C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model.
Results: Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant KRAS can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, KRAS promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. KRAS CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression.
Conclusions: In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134609 | PMC |
http://dx.doi.org/10.1186/s13046-022-02386-2 | DOI Listing |
Front Immunol
December 2024
Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians University, Munich, Germany.
CD8+ T cells are crucial cytotoxic components of the tumor immune system. In chronic inflammation, they become low-responsive, a state known as T cell exhaustion (TEX). The aim of immune checkpoint blockade is to counteract TEX, yet its dynamics in breast cancer remain poorly understood.
View Article and Find Full Text PDFJ Inflamm Res
December 2024
Department of Cardiothoracic Surgery, Changzheng Hospital, Naval Medical University, Shanghai, People's Republic of China.
Background: Cardiac macrophages are a heterogeneous population with high plasticity and adaptability, and their mechanisms in heart failure (HF) remain poorly elucidated.
Methods: We used single-cell and bulk RNA sequencing data to reveal the heterogeneity of non-cardiomyocytes and assess the immunoreactivity of each subpopulation. Additionally, we employed four integrated machine learning algorithms to identify macrophage-related genes with diagnostic value, and in vivo validation was performed.
Adv Sci (Weinh)
December 2024
Department of Rheumatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China.
Gouty arthritis is characterized by an acute inflammatory response triggered by monosodium urate (MSU) crystals deposited in the joints and periarticular tissues. Current treatments bring little effects owing to serious side effects, necessitating the exploration of new and safer therapeutic options. Macrophages play a critical role in the initiation, progression, and resolution of acute gout, with the cellular profiles closely linked to their activation and polarization.
View Article and Find Full Text PDFAutoimmun Rev
December 2024
Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, Luzhou, China; Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China. Electronic address:
Macrophage metabolic reprogramming has a central role in the progression of autoimmune and auto-inflammatory diseases. The heart is a major target organ in many autoimmune conditions and can sustain functional and structural impairments, potentially leading to irreversible cardiac damage. There is mounting clinical evidence pointing to a link between autoimmune disease and cardiac damage.
View Article and Find Full Text PDFJ Mol Cell Biol
December 2024
Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite treatment advances, the survival rates of high-risk NB patients remain low. This highlights the urgent need for a deeper understanding of the molecular mechanisms driving NB progression to support the development of new therapeutic strategies.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!