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fan Tong
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FP07 - Pathology (ID 109)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP07.01 - Dysbiosis of Gut Microbiota Suppress the Brain Metastasis of Non-Small Cell Lung Cancer (ID 1501)
00:00 - 00:00 | Author(s): fan Tong
- Abstract
Introduction
Brain metastasis (BM) is associated with poor prognosis in patients with advanced non-small cell lung cancer (NSCLC), gut microbiota have been reported involved in the development of NSCLC. However, the impact of the gut microbiota on BM of NSCLC is still vague to date. This study aimed to explore the potential mechanism of gut microbiota dysbiosis on BM of NSCLC.
Methods
We collected 85 fecal samples from NSCLC patients with or without BM, and performed 16S rRNA gene sequencing. Conventional C57BL/6 mice were treated with an antibiotic cocktail to deplete the gut microbiota. The effects of gut microbiota dysbiosis was investigated in vivo by using NSCLC BM mouse models.
Results
There are no obvious difference in the microbial diversity and composition between NSCLC patients with BM (BM+, n=25) and without BM group (BM-, n=60). However, several differentially abundant genera were identified between subject groups by LEfSe analysis and Wilcoxon rank-sum test. Blautia, the genus implicated in central nervous system disorder, significantly decreased in BM+ group comparing to BM- group. Furthermore, the tumor burden significantly reduced in antibiotics-treated BM mice model, along with increased microglia cells by flow cytometry analysis. Remarkably, fecal bacteria transplantation (FMT) reduced gut microbial dysbiosis, partially attenuate the antibiotic-mediated tumor inhibition.
Conclusion
These results indicate that gut microbiota dysbiosis modulate BM of NSCLC, and Blautia, was putative microbial biomarkers that exclusively associated with BM. Mice experiments suggest that gut microbial dysbiosis inhibit BM by increasing the number of microglia. FMT suggest that BM inhibition mediated by gut microbial disorder is weakened by restoring normal microbiota, and warrant further research on the function of microglia.
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P63 - Tumor Biology and Systems Biology - Basic and Translational Science - Metastases (ID 201)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P63.03 - M1 Phenotype Polarization of Microglia via MIF/CD74 Axis for Radiosensitization in NSCLC Brain Metastasis (ID 1158)
00:00 - 00:00 | Author(s): fan Tong
- Abstract
Introduction
Brain metastasis is a common complication with poor prognosis in non-small cell lung cancer (NSCLC). Radiotherapy, as the main treatment, still has unsatisfactory therapeutic effects. Microglia as brain macrophage displayed M1 or M2 phenotype depending on the microenvironment. Our previous study shows macrophage migration inhibitory factor (MIF) is overexpressed in primary tissues of NSCLC brain metastasis. Studies have reported that tumors escape M1 conversion of microglia via CD74 activation through the secretion of macrophage migration inhibitory factor (MIF). The aim of this study was to explore the effects of radiosensitization by inhibiting the MIF/CD74 axis to regulate the polarization of microglia to M1 phenotype in NSCLC brain metastasis.
Methods
The expression of MIF was detected in 4 NSCLC patients with brain metastasis and matched peritumoral tissues. ShRNA was applied to silence CD74 and MIF in BV2 cells and Lewis cells. M1 and M2 markers were detected by Western Blot, RT-PCR, immunofluorescence staining and flow cytometry. The phagocytosis of microspheres and Lewis cells in BV2 cells was detected by immunofluorescence staining and flow cytometry. The co-culture of Lewis and BV2 cells was constructed using transwell chambers. The wound healing and transwell assays were used to detect the migration of BV2 cells. The colony formation assay, Annexin V/7-AAD staining and PI staining were utilized to determine the effects of MIF/CD74 axis and HIF-1α/MIF on Lewis cells. In vivo model of brain metastasis was established to explore the effects of HIF-1α/MIF/CD74 signaling.
Results
The expression of MIF was significantly higher in brain tumors than peritumoral tissues, and high MIF expression indicated poor prognosis. Silencing CD74 promoted irradiated BV2 cells to M1 phenotype transformation. Co-culture of Lewis cells and irradiated BV2 cells showed that inhibition of MIF/CD74 axis promoted M1 polarization of BV2 cells, enhanced the ability of phagocytosis and migration in BV2 cells. Co-culture supernatant added to Lewis cells inhibited the proliferation and colony formation, induced apoptosis of Lewis cells. KC7F2 (HIF-1α inhibitor) inhibited MIF secretion and the binding of HIF-1α to MIF promoter in Lewis cells. Collecting the supernatant of Lewis cells with KC7F2 under hypoxic conditions, and added to irradiated BV2 cells knockdown CD74 for 24h. The results showed that inhibiting HIF-1α/MIF axis could transform BV2 cells to M1 phenotype, promoted the phagocytosis and migration of BV2 irradiated cells. Then, we collected the medium in BV2 cells, and applied to Lewis cells. We found that inhibition of HIF-1α/MIF/CD74 axis could inhibit the colony formation, remodel cell cycle distribution of Lewis cells, resulting cell apoptosis. The in vivo experiments indicated that radiation The in vivo experiments showed that inhibition of MIF/CD74 axis could improve hypoxia state of tumors and transform macrophages to M1 phenotype, leading to the shrinkage of brain tumors caused by radiotherapy, prolong survival time. Mechanically, we identified that MIF/CD74 pathway regulated phenotypic transformation of BV2 cells may by activating PI3K/AKT signaling.
Conclusion
The HIF-1α/MIF/CD74 axis could be used as a target for radiation therapy, providing a new research basis and theoretical basis for the treatment of NSCLC brain metastases.
