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Supplementary Materials and Methods, Supplementary Figures 1 through 3 and Supplementary Tables 1 through 5 from Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation

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posted on 2023-03-31, 01:10 authored by Ye Cui, Wendy K. Steagall, Anthony M. Lamattina, Gustavo Pacheco-Rodriguez, Mario Stylianou, Pranav Kidambi, Benjamin Stump, Fernanda Golzarri, Ivan O. Rosas, Carmen Priolo, Elizabeth P. Henske, Joel Moss, Souheil El-Chemaly

Supplementary methods. Supplementary Figure S1. R406 and rapamycin induce G1 cell cycle arrest in TSC2- cells. Supplementary Figure S2. Densitometric analysis of phospho-Syk and Syk, related to Fig. 4D. Supplementary Figure S3. TSC2 deficiency leads to upregulation of MCP-1 gene expression in vitro. Supplementary Table S1. Characteristics of subjects who were part of the longitudinal studies, related to Fig.6B. Supplementary Table S2. Characteristics of healthy volunteers and LAM subjects whose PBMCs were studied, related to Fig.6C. Supplementary Table S3. siRNA sequences. Supplementary Table S4. Complete list of antibodies. Supplementary Table S5. Real-time PCR primer sequences.

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Department of Defense

NIH

Lam Research

BRI

TSC

NHLBI

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ARTICLE ABSTRACT

Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphangioleiomyomatosis patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleiomyomatosis. In TSC2-deficient cells, Syk signaling increased the expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated the production of VEGF-D. In clinical isolates of PBMCs from lymphangioleiomyomatosis patients, VEGF-D expression was elevated. Furthermore, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for lymphangioleiomyomatosis growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation. Cancer Res; 77(6); 1492–502. ©2017 AACR.

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    Oncogenes & Tumor SuppressorsTumor suppressor genesPreclinical ModelsXenograft models

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