Data from <i>TSC2</i> Loss in Lymphangioleiomyomatosis Cells Correlated with Expression of CD44v6, a Molecular Determinant of Metastasis

作者：Gustavo Pacheco-Rodriguez, Wendy K. Steagall, Denise Crooks, Linda A. Stevens, Hiroshi Hashimoto, Shaowei Li, Ji-An Wang, Thomas N. Darling, Joel Moss · 年份：2026 · DOI：10.1158/0008-5472.c.8541901 · 研究领域：Tuberous Sclerosis Complex Research、Parasitic infections in humans and animals、Vascular Tumors and Angiosarcomas

<div>Abstract<p>Lymphangioleiomyomatosis (LAM), a rare multisystem disease found primarily in women of childbearing age, is characterized by the proliferation of abnormal smooth muscle–like cells, LAM cells, that form nodules in the pulmonary interstitium. Proliferation of LAM cells results, in part, from dysfunction in tuberous sclerosis complex (TSC) genes <i>TSC1</i> (hamartin) and/or <i>TSC2</i> (tuberin). Identification of LAM cells in donor lungs, their isolation from blood, and their presence in urine, chylous ascites, and pleural effusions are consistent with their ability to metastasize. Here, we investigated the presence on LAM cells of the hyaluronic acid receptor CD44 and its splice variants associated with metastasis. The heterogeneous populations of cells grown from lungs of 12 LAM patients contain cells expressing mRNA for the variant CD44v6. Histologically, CD44v6 was present in LAM lung nodules, but not in normal vascular smooth muscle cells. CD44v6-positive sorted cells showed loss of heterozygosity at the <i>TSC2</i> locus; binding of CD44v6 antibody resulted in loss of cell viability. Levels of CD44 were higher in cultured Eker rat (<i>Tsc2</i>−/−) cells than in <i>Tsc2</i>+/+ cells, but unlike human LAM cells, the <i>Tsc2</i>−/− Eker rat cells did not contain CD44v6 splice variant mRNA. CD44 splicing and signaling is regulated by osteopontin. Plasma from LAM patients conta...