Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules.

Koc-Gunel, S.; Gautam, L. K.; Calvert, B. A.; Murthy, S.; Harriott, N. C.; Nawroth, J. C.; Zhou, B.; Krymskaya, V. P.; Ryan, A. L.

doi:10.1101/2023.06.12.544372

bioRxiv · 10.1101/2023.06.12.544372

Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules.

Koc-Gunel, S.·Gautam, L. K.·Calvert, B. A.·Murthy, S.·Harriott, N. C.·Nawroth, J. C.·Zhou, B.·Krymskaya, V. P.·Ryan, A. L.

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Abstract

Lymphangioleiomyomatosis (LAM) is a progressive lung disease with limited treatments, largely due to an incomplete understanding of its pathogenesis. Lymphatic endothelial cells (LECs) invade LAM cell clusters, which include HMB-45-positive epithelioid cells and smooth muscle -actin-expressing LAM-associated fibroblasts (LAMFs). Recent evidence shows that LAMFs resemble cancer-associated fibroblasts, with LAMF-LEC interactions contributing to disease progression. To explore these mechanisms, we used spatial transcriptomics on LAM lung tissues and identified a gene cluster enriched in kinase signaling pathways linked to myofibroblasts and co-expressed with LEC markers. Kinase arrays revealed elevated PDGFR and FGFR in LAMFs. Using a 3D co-culture spheroid model of primary LAMFs and LECs, we observed increased invasion in LAMF-LEC spheroids compared to non-LAM fibroblasts. Treatment with sorafenib, a multikinase inhibitor, significantly reduced invasion, outperforming Rapamycin. We also confirmed TSC2-null AML cells as key VEGF-A secretors, which was suppressed by sorafenib in both AML cells and LAMFs. These findings highlight VEGF-A and bFGF as potential therapeutic targets and suggest multikinase inhibition as a promising strategy for LAM. One Sentence SummaryUsing 3D spheroids and spatial transcriptomics, we identified LAMFs and LECs as key contributors to LAM, with bFGF and VEGF-A as potential therapeutic targets

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Koc-Gunel, S., Gautam, L. K., Calvert, B. A., Murthy, S., Harriott, N. C., Nawroth, J. C., Zhou, B., Krymskaya, V. P., Ryan, A. L.. 2023-06-12. Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules.. https://doi.org/10.1101/2023.06.12.544372

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