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.

Although chemotherapy is an important treatment for advanced prostate cancer, its efficacy is relatively limited. Ultrasound-induced cavitation plays an important role in drug delivery and gene transfection. However, whether cavitation can improve the efficacy of chemotherapy for prostate cancer remains unclear. In this study, we treated RM-1 mouse prostate carcinoma cells with a combination of ultrasound-mediated microbubble cavitation and paclitaxel. Our results showed that combination therapy led to a more pronounced inhibition of cell viability and increased cell apoptosis. The enhanced efficacy of chemotherapy was attributed to the increased cell permeability induced by cavitation. Importantly, compared with chemotherapy alone (nab-paclitaxel), chemotherapy combined with ultrasound-mediated microbubble cavitation significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice in an orthotopic mouse model of RM-1 prostate carcinoma, indicating the synergistic effects of combined therapy on tumor reduction. Furthermore, we analyzed tumor-infiltrating lymphocytes and found that during chemotherapy, the proportions of CTLA4 cells and PD-1/CTLA4 cells in CD8 T cells slightly increased after cavitation treatment.

Ultrasound-mediated microbubbles cavitation enhanced chemotherapy of advanced prostate cancer by increasing the permeability of blood-prostate barrier.

 Ischemic stroke poses a significant health burden with limited treatment options. Lymphocyte Cytosolic Protein 1 (LCP1) facilitates cell migration and immune responses by aiding in actin polymerization, cytoskeletal rearrangements, and phagocytosis. We have demonstrated that the long non-coding RNA (lncRNA) Maclpil silencing in monocyte-derived macrophages (MoDMs) led to LCP1 inhibition, reducing ischemic brain damage. However, the role of LCP1 of MoDMs in ischemic stroke remains unknown.  We investigated the impact of LCP1 on ischemic brain injury and immune cell signaling and metabolism. We found that knockdown of LCP1 in MoDMs demonstrated robust protection against ischemic infarction and improved neurological behaviors in mice. Utilizing the high-dimensional CyTOF technique, we demonstrated that knocking down LCP1 in MoDMs led to a reduction in neuroinflammation and attenuation of lymphopenia, which is linked to immunodepression. It also showed altered immune cell signaling by modulating the phosphorylation levels of key kinases and transcription factors, including p-PLCg2, p-ERK1/2, p-EGFR, p-AKT, and p4E-BP1 as well as transcription factors like p-STAT1, p-STAT3, and p-STAT4. Further bioinformatic analysis indicated that Akt and EGFR are particularly involved in fatty acid metabolism and glycolysis. Indeed, single-cell sequencing analysis confirmed that enrichment of fatty acid and glycolysis metabolism in Lcp1 monocytes/macrophages. Furthermore, Lcp1 cells exhibited enhanced oxidative phosphorylation, chemotaxis, migration, and ATP biosynthesis pathways.  experiments confirmed the role of LCP1 in regulating mitochondrial function and fatty acid uptake.  These findings contribute to a deeper understanding of LCP1 in the context of ischemic stroke and provide valuable insights into potential therapeutic strategies targeting LCP1 and metabolic pathways, aiming to attenuating neuroinflammation and lymphopenia.

LCP1 knockdown in monocyte-derived macrophages: mitigating ischemic brain injury and shaping immune cell signaling and metabolism.

It has been estimated that one in four stroke patients may have recurrent stroke within five years after they experienced the first stroke. Furthermore, clinical studies have shown that recurrent stroke negatively affects patient outcomes; the risk of disability and the death rate increase with each recurrent stroke. Therefore, it is urgent to find effective methods to prevent recurrent stroke. The gut microbiota has been proven to play an essential role after ischemic stroke, while sudden ischemia disrupts microbial dysbiosis, and the metabolites secreted by the microbiota also reshape the gut microenvironment. In the present study, we established a recurrent ischemic mouse model. Using this experimental model, we compared the survival rate and ischemic infarction between single MCAO and recurrent MCAO, showing that, when two surgeries were performed, the mouse survival rate dramatically decreased, while the infarction size increased. Fecal samples were collected on day 1, day 3 and day 7 after the first MCAO and day 9 (2 days after the second MCAO) for 16S sequencing, which provided a relatively comprehensive picture of the microbiota changes. By further analyzing the potential metabolic pathways, our data also highlighted several important pathways that were significantly altered after the first and recurrent stroke. In the present study, using an experimental mouse model, we showed that acute ischemic stroke, especially recurrent ischemia, significantly decreased the diversity of the gut microbiota.

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
Ultrasound-mediated microbubbles cavitation enhanced chemotherapy of advanced prostate cancer by increasing the permeability of blood-prostate barrier. Translational oncology\| PubMed ID: 34271256	2021
LCP1 knockdown in monocyte-derived macrophages: mitigating ischemic brain injury and shaping immune cell signaling and metabolism. Theranostics\| PubMed ID: 38164159	2024
Systemic Characterization of the Gut Microbiota Profile after Single Mild Ischemic Stroke and Recurrent Stroke in Mice. Biomedicines\| PubMed ID: 38255299	2024

Decao Yang

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