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  • American Association for Cancer Research (AACR)  (2)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2767-2767
    Abstract: Melanoma is a skin cancer at high risk of metastatic progression, hence associated with poorer prognosis. Imaging represents an essential tool to assess tumor stage, but also to monitor disease progression and therapy response. However, a single imaging technique cannot efficiently detect and characterize all metastases. Therefore, we evaluated the potential of simultaneous 18F-FDG PET/MR imaging in preclinical models of disseminated melanoma at different stages. Female Nude and SDRG rats were intravenously injected with CMEL 5 cells, originating from brain metastases of a human melanoma. On day (D) 60, 70, and 80 post-injection, Nude rats were imaged using brain T2-weighted (T2w) 7T MRI and whole-body simultaneous 18F-FDG (10-15 MBq) PET/MR. Furthermore, whole-body and brain T2w MR images were acquired using a 4.7T MRI on D20 and D34 post-injection in SDRG rats. Visual detection and quantitative analysis of lesions were performed on MRI or PET/MR images, and results were confronted with necropsy (melanin pigmented lesions) and gamma counting data. From D60 post-CMEL-5 cell injection, all Nude animals exhibited metastases in one to four different locations. Moreover, most of metastases locations found in clinical setting were detected in our experimental model using simultaneous 18F-FDG PET/MR imaging, even allowing the observation of brain lesions on T2w MR images. MRI further allowed precise contouring of each organ of interest to effectively identify bone, lung, adrenal and spleen metastases with enhanced 18F-FDG uptake. Additionally, PET image quantification in adrenals was consistent with gamma counting results. As anticipated, small lesions below PET spatial resolution limit (i.e. & lt;1 mm) were not detected by imaging. SDRG rats displayed a faster and more homogenous tumor spread in brain, lungs and liver on MR images, while more metastases were seen during autopsy (additional spreading to pancreas, adrenals, reproductive system, bones, lymph nodes and skin). The experimental model of disseminated CMEL-5 melanoma in Nude rats demonstrates its ability to mimic the human pathology. Hence, it appears to be a promising tool to monitor therapy response and potentially recognize progression from pseudo-progression. Simultaneous PET/MR imaging has shown to be more effective than stand-alone techniques in detecting melanoma dissemination, except for brain and small lesions for which the PET data are altered by partial volume effect. Thus, by complementing previously acquired MR images from the novel SDRG rat model with simultaneously acquired PET images, we could also provide insights on this promising metastatic model. Citation Format: Alexandra Oudot, Peggy Provent, Alan Courteau, Nicolas Hoffmann, Melanie Guillemin, Jordan Longin, Sarah Belderbos, Bertrand Collin, Marc Hillairet de Boisferon, Alexandre Cochet, Cyril Berthet. Simultaneous 18F-FDG PET/MR imaging for metastases identification in a disseminated human preclinical melanoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2767.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
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    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2434-2434
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2434-2434
    Abstract: Introduction: The Hippo pathway effector YAP contributes to carcinogenesis by directing stem cell activity, cell proliferation and cell survival signals. In the lung, aberrant nuclear YAP activity promotes bronchial epithelial growth, which in animal models can drive pathology that resembles lung premalignant lesions (PMLs). However, the molecular mechanisms by which YAP contributes to aberrant lung epithelial pathology are poorly understood. In this project, we investigated the DNA binding pattern and gene expression program regulated by YAP and associated TEAD and TP63 transcriptional factors in primary normal human bronchial epithelial cells (HBECs) and lung cancer cell lines. Methods: RNA-seq experiments were conducted using HBEC, H2170 and SW900 cells transfected with siRNA targeting YAP, TEADs or TP63, and expression profiles were compared to corresponded controls to derive gene signatures. In parallel, ChIP-seq experiments were carried out using antibodies specific for the respective proteins to identify genome binding peaks. Direct target genes were inferred with Binding and Expression Target Analysis (BETA) using gene signature and peak profile of each factor in each cell line respectively. The metagene score for target genes in longitudinally collected endobronchial biopsies from patients with PMLs was calculated using GSVA and the association with PML phenotypes was tested with a mixed-effects model adjusting for batch and patient as random effect (GSE109743). Results: Chromatin binding analyses revealed that YAP co-occupies genomic regions with TEAD and TP63 in normal bronchial epithelial cells aligning with H3K27ac chromatin modifications. Integrating genomic binding and gene expression profiling, we identified large overlaps in target genes directly regulated by YAP, TEAD and TP63 in HBECs, demonstrating cooperation between these factors in the control of bronchial epithelial transcription. YAP-TEAD-TP63 induced targets in HBECs are enriched for genes involved in cell proliferation and extracellular matrix alteration, while repressed targets are enriched for genes involved in cell fate specification. Notably, cooperatively regulated genes are strongly associated with gene expression profile identified in progressive PML, and in particular with genes linked to early immune responses that are observed with PML pathology progression. Similar analyses of YAP, TEAD and TP63 in lung cancer cells revealed an altered transcriptional program for YAP with a divergence of YAP-TEAD away from TP63, suggesting contextual changes in YAP activity with cancer progression. Conclusion: We found that YAP, TP63 and TEADs co-regulate lung epithelial gene expression related to PML pathology progression. These findings provide insight into potential YAP function in the early stages of lung carcinogenesis and offer potential new avenues to develop lung cancer interception strategies. Citation Format: Boting Ning, Andrew Tilston-Lunel, Julia Hicks-Berthet, Sarah A. Mazzilli, Jennifer E. Beane, Xaralabos Varelas, Marc E. Lenburg. Transcriptional crosstalk between YAP, TEAD and TP63 is associated with early lung carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2434.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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