Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules

Sinem Koc-Gunel; Lalit K. Gautam; Ben A Calvert; Shubha Murthy; Noa C. Harriott; Janna C. Nawroth; Beiyun Zhou; Vera P. Krymskaya; Amy L. Ryan

doi:10.1101/2023.06.12.544372

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Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules

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Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules

Sinem Koc-Gunel, Lalit K. Gautam, Ben A Calvert, Shubha Murthy, Noa C. Harriott, Janna C. Nawroth, Beiyun Zhou, Vera P. Krymskaya and Amy L. Ryan

bioRxiv

Cold Spring Harbor Laboratory

06/12/2023

DOI: 10.1101/2023.06.12.544372

PMCID: PMC10312665

PMID: 37398026

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https://doi.org/10.1101/2023.06.12.544372View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

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.

Details

Title: Subtitle: Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules
Creators: Sinem Koc-Gunel - University of Southern California
Lalit K. Gautam - University of Iowa
Ben A Calvert - University of Iowa
Shubha Murthy - University of Iowa
Noa C. Harriott - University of Iowa
Janna C. Nawroth - University of Southern California
Beiyun Zhou - University of Southern California
Vera P. Krymskaya - University of Pennsylvania
Amy L. Ryan - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2023.06.12.544372
PMID: 37398026
PMCID: PMC10312665
Publisher: Cold Spring Harbor Laboratory
Language: English
Date posted: 06/12/2023
Academic Unit: Anatomy and Cell Biology
Record Identifier: 9984438902402771

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