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

Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes. However, genes that specifically promote basal-like breast cancer development remain largely unknown. Here, we report that a novel gene C1orf106 plays an important role in maintaining the feature of basal-like/luminal progenitors. C1orf106 is frequently amplified and overexpressed in basal-like breast cancer and is associated with a poor outcome in patients. In human TCGA database, C1orf106 expression was correlated with upregulation of ELF5 and downregulation of GATA3, two transcription factors that regulate mammary gland stem cell fate. Enhanced expression of C1orf106 promotes tumor progression and expression of basal-like/luminal progenitor marker ELF5; depletion of C1orf106 suppresses tumorigenesis and expression of basal-like/luminal progenitor marker GATA3. These findings suggest that C1orf106 maintains the basal-like/luminal progenitor character through balancing the expression of ELF5 and GATA3. Taken together, we demonstrated that C1orf106 is an important regulator for basal-like/luminal progenitors and targeting C1orf106 is of therapeutic value for breast cancer.

C1orf106, an innate immunity activator, is amplified in breast cancer and is required for basal-like/luminal progenitor fate decision.

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.

Cholesterol and its metabolites have important biological functions. Cholesterol is able to maintain the physical properties of cell membrane, play an important role in cellular signaling, and cellular cholesterol levels reflect the dynamic balance between biosynthesis, uptake, efflux and esterification. Cholesterol metabolism participates in bile acid production and steroid hormone biosynthesis. Increasing evidence suggests a strict link between cholesterol homeostasis and tumors. Cholesterol metabolism in tumor cells is reprogrammed to differ significantly from normal cells, and disturbances of cholesterol balance also induce tumorigenesis and progression. Preclinical and clinical studies have shown that controlling cholesterol metabolism suppresses tumor growth, suggesting that targeting cholesterol metabolism may provide new possibilities for tumor therapy. In this review, we summarized the metabolic pathways of cholesterol in normal and tumor cells and reviewed the pre-clinical and clinical progression of novel tumor therapeutic strategy with the drugs targeting different stages of cholesterol metabolism from bench to bedside.

The role of cholesterol metabolism in tumor therapy, from bench to bed.

FDA issued guidance on April 10th, 2025 to phase out animal trials in favor of organoids and organ-on-a-chip systems. This pivotal move was swiftly followed by National Institutes of Health (NIH) on April 29th, when it inaugurated the Office of Research Innovation, Validation, and Application (ORIVA). The establishment of ORIVA aims to spearhead the advancement of human-centric organ-on-a-chip technologies, marking a major stride toward more accurate, ethical, and efficient research methods in the biomedical field. Compared to traditional 2D cell cultures and animal models, organ-on-a-chip systems enable precise control of hydrodynamic parameters and biomechanical microenvironments. This review systematically elaborates on applications of single-organ, multi-organ, and organoid-on-a-chip technologies in modeling complex diseases, host-microbiome interactions, inter-organ physiological networks, and quantitative prediction of pharmacokinetics, toxicity responses, and personalized therapies. Furthermore, the core challenges in translating these technologies to pharmaceutical development and clinical practice are critically analyzed. With interdisciplinary integration of materials engineering, biosensing, and artificial intelligence, organ-on-a-chip technologies are transcending the limitations of conventional preclinical research. Their strategic value as 'patient surrogates' is poised to accelerate breakthroughs in precision medicine and rare disease treatments.

Synergistic innovation in organ-on-a-chip and organoid technologies: Reshaping the future of disease modeling, drug development and precision medicine.

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.

Exosomal PD-L1 detection in cancer predictive biomarker for response to immune checkpoint blockade therapy.

Ovarian cancer represents the most aggressive and lethal gynecological cancer, frequently demonstrating a distinct propensity for abdominal metastasis. Malignant ascites caused by abdominal metastasis provide a tumor microenvironment (TME) in ovarian cancer. Notably, oleic acid is abundant in ovarian cancer ascites, though its functional significance in TME modulation and tumor metastatic regulation remains poorly characterized. Stearoyl-CoA desaturase 1 (SCD1) is the key enzyme in the synthesis of oleic acid. Our study systematically explores the pathological role of oleic acid and evaluates the therapeutic effects of SCD1 inhibitor in ovarian cancer progression.

Oleic acid activates TGFβ-Smad3 signaling to promote ovarian cancer progression.

Ovarian cancer (OC) is the most aggressive and lethal gynaecological cancer and is characterised by abnormal lipid metabolism. Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2). It functions as a tumour promoter through both canonical H3K27me3 modification and noncanonical mechanisms. Although EZH2 has been developed as a potential anticancer target, the therapeutic effects of EZH2 inhibitors in solid tumours are still limited.

Article	Year
C1orf106, an innate immunity activator, is amplified in breast cancer and is required for basal-like/luminal progenitor fate decision. Science China. Life sciences\| PubMed ID: 31376015	2019
EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment. Frontiers in immunology\| PubMed ID: 35432300	2022
The role of cholesterol metabolism in tumor therapy, from bench to bed. Frontiers in pharmacology\| PubMed ID: 37089950	2023
Synergistic innovation in organ-on-a-chip and organoid technologies: Reshaping the future of disease modeling, drug development and precision medicine. Protein & cell\| PubMed ID: 40653861	2025
Exosomal PD-L1 detection in cancer predictive biomarker for response to immune checkpoint blockade therapy. Frontiers in immunology\| PubMed ID: 40677702	2025
Oleic acid activates TGFβ-Smad3 signaling to promote ovarian cancer progression. Journal of ovarian research\| PubMed ID: 40790593	2025
Differential regulation of FADS2 by EZH2 reveals a metabolic vulnerability in ovarian cancer treatment. EBioMedicine\| PubMed ID: 40818202	2025

Jiagui Song

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