advancements-metabolic-profiling-three-dimensional-brain-tumor

Advancements in the Metabolic Profiling of Three-Dimensional Brain Tumor Spheroids for Drug Screening

Brain tumors, especially gliomas, are challenging to treat because of their aggressive nature, complex tumor microenvironment, and resistance to ...

Peking University Third Hospital

Cancer Center of Peking University Third Hospital

As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for CVD. Accumulated studies have shown that hypercholesterolemia is associated with myeloid cell expansion, which stimulates innate and adaptive immune responses, strengthens inflammation, and accelerates atherosclerosis progression. Hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) expresses a panel of lipoprotein receptors to control cholesterol homeostasis. Deficiency of these receptors abrogates cellular cholesterol efflux, resulting in HSPC proliferation and differentiation in hypercholesterolemic mice. Reduction of the cholesterol level in the lipid rafts by infusion of reconstituted high-density lipoprotein (HDL) or its major apolipoprotein, apoA-I, reverses hypercholesterolemia-induced HSPC expansion. Apart from impaired cholesterol metabolism, inhibition of reactive oxygen species production suppresses HSPC activation and leukocytosis. These data indicate that the mechanisms underlying the effects of hypercholesterolemia on HSPC proliferation and differentiation could be multifaceted. Furthermore, dyslipidemia also regulates HSPC-neighboring cells, resulting in HSPC mobilization. In the article, we review how hypercholesterolemia evokes HSPC activation and mobilization directly or via its modification of BM microenvironment. We hope this review will bring light to finding key molecules to control HSPC expansion, inflammation, and atherosclerosis for the treatment of CVD.

Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis.

Sensitivity has been a key issue for Enhancer of zeste homolog 2 (EZH2) inhibitors in cancer therapy. The EZH2 inhibitor EPZ-6438 was first approved by the US Food and Drug Administration (FDA) in 2020. However, its inadequate anti-cancer activity in solid tumors limits its clinical application. In this study, we utilized the multiple cancer cell lines, which are less sensitive to the EZH2 inhibitor GSK126, combining animal model and clinical data to investigate the underlying mechanism.

Dysregulated lipid metabolism blunts the sensitivity of cancer cells to EZH2 inhibitor.

EZH2 inhibitors (EZH2i), a class of small-molecule inhibitors that target EZH2 to exert anti-tumor functions, have just been approved by the US Food and Drug Administration (FDA) in treatment of adults and adolescents with locally advanced or metastatic epithelioid sarcoma. The application of EZH2i in several solid tumors is still in different stages of clinical trials and needs to be further validated. As a key epigenetic regulator, besides its role in controlling the proliferation of tumor cells, EZH2 has been implicated in the regulation of various immune cells including macrophages. But there are still controversial research results at present. Colorectal cancer (CRC) is a common malignant tumor that highly expresses EZH2, which has the third highest incidence and is the second leading cause of cancer-related death worldwide. Studies have shown that the numbers of M2-type tumor-associated macrophages (TAMs) are highly associated with the progression and metastasis of CRC. In the current study, we aim to investigate how EZH2 modulates the polarization of macrophages in the tumor microenvironment (TME) of CRC, and compare the role of two different EZH2 inhibitors, EPZ6438 and GSK126. We applied a 3D culture method to demonstrate that EZH2i did indeed suppress the proliferation of CRC cells . , we found that the percentage of CD206 macrophages of the TME was decreased under the treatment of EPZ6438, but it increased upon GSK126 treatment. Besides, in the co-culture system of macrophages and CRC cells, EPZ6438 led to significant elevation of M1 markers and reduction of M2 markers. Furthermore, mechanistic studies validated by ChIP-qPCR demonstrated that EZH2i inhibit EZH2-mediated H3K27me3 levels on the promoters of STAT3, an essential transcription factor for M1 macrophage polarization. Therefore, our data suggested that EZH2i not only suppress CRC cell proliferation directly, but also regulate macrophage by skewing M2 into effector M1 macrophage to exert a tumor suppressive effect. Moreover, our study provided new insight for better understanding of the role of two kinds of EZH2i: EPZ6438 and GSK126, which may pave the way in treating CRC by targeting cancer cells and immune cells  this epigenetic approach in the future.

EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment.

Hyperglycemia-induced myelopoiesis and atherosclerotic progression occur in mice with type I diabetes. However, less is known about the effects of metabolites on myelopoesis in type 2 diabetes. Here, we use fluorescence-activated cell sorting to analyze the proliferation of granulocyte/monocyte progenitors (GMP) in db/db mice. Using targeted metabolomics, we identify an increase in inosine monophosphate (IMP) in GMP cells of 24-week-old mice. We show that IMP treatment stimulates cKit expression, ribosomal S6 activation, GMP proliferation, and Gr-1 granulocyte production in vitro. IMP activates pAkt in non-GMP cells. In vivo, using an established murine acute pancreatitis (AP) model, administration of IMP-treated bone marrow cells enhances the severity of AP. This effect is abolished in the presence of a pAkt inhibitor. Targeted metabolomics show that plasma levels of guanosine monophosphate are significantly higher in diabetic patients with AP. These findings provid a potential therapeutic target for the control of vascular complications in diabetes.

The purine metabolite inosine monophosphate accelerates myelopoiesis and acute pancreatitis progression.

Beyond glycemic control, applications of glucagon-like peptide-1 receptor (GLP-1r) agonists (GLP-1 RAs) inhibit inflammation and plaque development in murine atherosclerotic models. However, whether they modulate hematopoietic stem/progenitor cells (HSPCs) to prohibit skewed myelopoiesis in hypercholesteremia remains unknown. In this study, GLP-1r expression in fluorescence-activated cell sorting (FACS)-sorted wild-type HSPCs was determined by capillary western blotting. Bone marrow cells (BMCs) of wild-type or GLP-1r-/- mice were transplanted into lethally irradiated low-density lipoprotein receptor deficient (LDLr-/-) recipients followed by high-fat diet (HFD) for chimerism analysis by FACS. In parallel, LDLr-/- mice were placed on HFD for 6 weeks and then treated with saline or Exendin-4 (Ex-4) for another 6 weeks. HSPC frequency and cell cycle were analyzed by FACS, and intracellular metabolite levels were assessed by targeted metabolomics. The results demonstrated that HSPCs expressed GLP-1r and transplantation of GLP-1r-/- BMCs resulted in skewed myelopoiesis in hypercholesterolemic LDLr-/- recipients. In vitro, Ex-4 treatment of FACS-purified HSPCs suppressed cell expansion and granulocyte production induced by LDL. In vivo, Ex-4 treatment inhibited plaque progression, suppressed HSPC proliferation, and modified glycolytic and lipid metabolism in HSPCs of hypercholesteremic LDLr-/- mice. In conclusion, Ex-4 could directly inhibit HSPC proliferation induced by hypercholesteremia.

Exendin-4 attenuates atherosclerosis progression via controlling hematopoietic stem/progenitor cell proliferation.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype-phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of  (c.86A>G) in one of the probands. This finding is significant as mutations in the  gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring  mutations. In conclusion, our study contributes to the growing body of evidence linking  to ALS and enhances our understanding of the intricate genetic landscape of this disease.

Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of  in Chinese Patients with Familial Amyotrophic Lateral Sclerosis.

Programmed death-ligand 1 (PD-L1) carried by tumor-derived exosomes has emerged as a critical mediator of immune evasion and resistance to immune checkpoint blockade therapy. Unlike membrane-bound PD-L1, exosomal PD-L1 is systemically distributed and capable of suppressing T cell activity at distant sites. This review summarizes the current understanding of exosomal PD-L1 biogenesis, its immunosuppressive mechanisms, and its clinical relevance across multiple cancer types. We highlight its potential as a non-invasive biomarker for predicting therapeutic response and monitoring disease progression. Compared with tissue-based PD-L1 assessment, exosomal PD-L1 offers advantages in accessibility and dynamic reflection of tumor immune status. However, challenges remain regarding standardization of detection methods and clinical interpretation. Future directions include the integration of exosomal PD-L1 profiling into immunotherapy decision-making and the development of therapeutic strategies targeting exosome secretion. These insights may contribute to overcoming resistance in immunologically inert tumors and advancing precision oncology.

Article	Year
Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis. International journal of molecular sciences\| PubMed ID: 27447612	2016
Dysregulated lipid metabolism blunts the sensitivity of cancer cells to EZH2 inhibitor. EBioMedicine\| PubMed ID: 35158113	2022
EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment. Frontiers in immunology\| PubMed ID: 35432300	2022
The purine metabolite inosine monophosphate accelerates myelopoiesis and acute pancreatitis progression. Communications biology\| PubMed ID: 36224248	2022
Exendin-4 attenuates atherosclerosis progression via controlling hematopoietic stem/progenitor cell proliferation. Journal of molecular cell biology\| PubMed ID: 36866528	2023
Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of in Chinese Patients with Familial Amyotrophic Lateral Sclerosis. Genes\| PubMed ID: 38927616	2024
Exosomal PD-L1 detection in cancer predictive biomarker for response to immune checkpoint blockade therapy. Frontiers in immunology\| PubMed ID: 40677702	2025

Xiaojuan Ma

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