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Jiaojiao Wang



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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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      P63.04 - Dysbiosis of Sputum and Gut Microbiota Modulate Development and Distant Metastasis of Non-Small Cell Lung Carcinomas (ID 1584)

      00:00 - 00:00  |  Presenting Author(s): Jiaojiao Wang

      • Abstract
      • Slides

      Introduction

      Lung cancer (LC) is the leading cause of cancer-related deaths mortality worldwide, with non-small cell lung cancer (NSCLC) being the most common form of LC. Despite the recent development of therapies for NSCLC, tumor metastasis is the main cause of recurrence and mortality in patients with NSCLC. Although dysbiosis of lung and gut microbiota have been associated with NSCLC, their relative contributions are unclear. In addition, their roles in distant metastasis (DM) are still illusive.

      Methods

      We enrolled in total 121 individuals who completed our study protocol. Among which, 87 were newly diagnosed with NSCLC who had not previously received any anticancer therapy nor treated with any antibiotics, while 34 were healthy volunteers. We classified patients into distinct disease stages (i.e. from I to IV) according to the 8th American Joint Committee on Cancer guidelines. Then, we collected in total 30 sputum and 29 fecal samples from the healthy controls and 66 sputum and 85 fecal samples from the NSCLC patients, and submitted them for 16S sequencing. To further validate microbiota play important roles in the development of NSCLC, we treated C57BL/6 adult female mice (six weeks of age) with antibiotic cocktail (ABX) of vancomycin, neomycin, ampicillin and metronidazol in drinking water starting 2 weeks before tumor inoculation. Subcutaneous tumor model was established by injecting murine Lewis lung cancer cell tagged with luciferences (LLC-luc) in the subcutaneous layer of C57BL/6 mice's right back.

      Results

      We found significant perturbations of gut- and sputum- microbiota in patients with NSCLC and DM. We obtained better Machine-learning models for patient stratification using both microbiota than either dataset, with the highest area under the curve (AUC) value of 0.842; surprisingly, sputum- microbiota contributed more than the gut. Several microbial-biomarkers were shared by both microbiota, indicating their similar roles at distinct body sites. Microbial-biomarkers of distinct disease stages were mostly shared, suggesting biomarkers for distant metastasis could be acquired early. Surprisingly, Pseudomonas aeruginosa, a species previously associated with wound infections, was associated with brain metastasis, indicating distinct types of DMs could have different microbial-biomarkers. Furthermore, we found significantly larger tumors in antibiotics-treated mice, confirming that microbiota dysbiosis could indeed promote tumor growth.

      Conclusion

      Our results indicate that in addition to gut-microbiota, sputum-microbiota could contribute significantly to NSCLC and distant metastasis, and improve the performance of patient-stratification models. Mice experiments suggest that favorable clinical outcomes could be accomplished by restoring normal microbiota, and warrant further research on the underlying molecular mechanisms.

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    P71 - Tumor Biology and Systems Biology - Basic and Translational Science - RTK/VEGF (ID 212)

    • 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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      P71.01 - The Effects of Vascular Endothelial Cells on Regulating Post-Irradiation Microglia Phenotype in Irradiation-Induced Brain Injury         (ID 1566)

      00:00 - 00:00  |  Presenting Author(s): Jiaojiao Wang

      • Abstract
      • Slides

      Introduction

      Radiation-induced brain injury (RIBI) is a common and devastating complication associated with cancer patients receiving cranial radiation therapy (CRT). Activated microglia and vascular injury are considered to play pivotal roles in the pathogenesis of RIBI. In the current study, we discovered that in the hippocampus perivascular, microglia were activated after 10 grays CRT and started to expand cellular protrusions towards adjacent blood vessels. The findings raises the questions of the functional relevance of the association of microglia with injured blood vessels after CRT.

      Methods

      The ultrastructural blood vessels in the hippocampus were examined by transmission electron microscopy. Immunofluorescence staining (IF) was used to explore the dynamics of microglial activation and its relationship with injured blood vessels in the hippocampus. EMSA and dual luciferase assays were performed to confirm the transcriptional activation of NF-κB induced by radiation in HUVECs. Migration and co-culture assays were used to investigate the possible mechanism on the association between HUVEC and BV-2 cell after irradiation. BV-2 cell, cultured for 3h with or without fractalkine (FKN 100ng/ml), received 10 Gy irradiation. Moreover, the CX3CR1 (the receptor of FKN on microglia) wide-type (CX3CR1WT) and CX3CR1-knockdown (CX3CR1-/-) mice were employed and subjected to lateral ventricular injection (ICV) of 5 μl FKN lentivirus or vector 3 days before CRT. And then, the in vitro and in vivo phenotype transformation of microglia and its inflammatory factors release were detected by western blotting, real-time PCR, ELISA and IF at different time-points after irradiation. Morris water maze test was used to test the cognitive function in mice.

      Results

      In the hippocampus of the CRT group, we observed that the endothelial cells were not arranged as closely as open cell-cell tight junctions, which were characterized by intralumenal protrusion of endothelial cells. In vitro migration and co-culture assays demonstrated molecular signals, secreted by vascular endothelial cells (ECs) via NF-κB pathway leading to the activation of microglia and their recruitment to blood vessels. ELISA and qRT-PCR revealed that radiation promoted the secretion of FKN from the vascular ECs via activating the NF-κB pathway. Western blotting and Flow cytometry showed that treatment with exogenous FKN promoted microglia M2 phenotype transformation, diminished radiation-induced proinflammatory factors, and enhanced phagocytosis capacity after radiation. In addition, up-regulation of FKN via FKN lentivirus promoted radiation-induced microglial M2 transformation in the hippocampus, and diminished the spatial memory injury of radiated mice. Lastly, while inhibiting the CX3CR1, which is exclusively expressed on microglia in the brain, the regulatory effect of FKN on microglia and cognitive ability of mice disappeared after radiation.

      Conclusion

      Our study has unveiled an important and novel role of FKN/CX3CR1 in RIBI, the FKN mainly secreted by vascular ECs after irradiation may attenuate RIBI through the microglia polarization toward M2 phenotype by binding to CX3CR1 on microglia.

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