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| Status |
Public on Jun 13, 2024 |
| Title |
Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Lymphangioleiomyomatosis (LAM) is a debilitating, progressive lung disease with few therapeutic options, largely due to a paucity of mechanistic knowledge of disease pathogenesis. Lymphatic endothelial cells (LECs) are known to envelope and invade clusters of LAM-cells, comprising of smooth muscle α-actin and/or HMB-45 positive "smooth muscle-like cells” however the role of LECs in LAM pathogenesis is still unknown. To address this critical knowledge gap, we investigated wether LECs interact with LAM-cells to augment their metastatic behaviour of LAM-cells. We performed in situ spatialomics and identified a core of transcriptomically related cells within the LAM nodules. Pathway analysis highlights wound and pulmonary healing, VEGF signaling, extracellular matrix/actin cytoskeletal regulating and the HOTAIR regulatory pathway enriched in the LAM Core cells. We developed an organoid co-culture model combining primary LAM-cells with LECs and applied this to evaluate invasion, migration, and the impact of Sorafenib, a multi-kinase inhibitor. LAM-LEC organoids had significantly higher extracellular matrix invasion, decreased solidity and a greater perimeter, reflecting increased invasion compared to non-LAM control smooth muscle cells. Sorafenib significantly inhibited this invasion in both LAM spheroids and LAM-LEC organoids compared to their respective controls. We identified TGFβ1ι1, a molecular adapter coordinating protein-protein interactions at the focal adhesion complex and known to regulate VEGF, TGFβ and Wnt signalling, as a Sorafenib-regulated kinase in LAM-cells. In conclusion we have developed a novel 3D co-culture LAM model and have demonstrated the effectiveness of Sorafenib to inhibit LAM-cell invasion, identifying new avenues for therapeutic intervention.
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| Overall design |
Spatial Transcriptome sequencing libraries were prepared with 10x Genomic Visium Spatial Gene Expression Slides & reagent kit according to the manufacturers instructions
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| Contributor(s) |
Ryan AL, Koc-Gunel S, Gautam LK, Calvert BA, Murthy S, Harriott NC, Nawroth JC, Zhou B, Krymskaya VP |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Jun 14, 2023 |
| Last update date |
Jun 13, 2024 |
| Contact name |
Amy Leanne Ryan |
| E-mail(s) |
amy-l-ryan@uiowa.edu
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| Phone |
13193358908
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| Organization name |
The University of Iowa
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| Department |
Anatomy and Cell Biology
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| Lab |
Ryan Laboratory
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| Street address |
51 Newton Road
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| City |
Iowa City |
| State/province |
IA |
| ZIP/Postal code |
52242-1009 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA983678 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE234885_RAW.tar |
8.3 Gb |
(http)(custom) |
TAR (of CLOUPE, CSV, H5, JPG, JSON, PNG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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