We used microsatellite marker fingerprinting and TSC2 gene mutational analysis to study a patient with recurrent LAM after single-lung transplantation.
Using immunohistochemistry and single-cell flow cytometry, we found increased PD-L1 expression both in human lung tissue from patients with LAM and in Tsc2-null lesions in a murine model of LAM.
Immunohistochemical stains of both LAM and renal angiomyolipoma showed positive immunoreactivity for hamartin (TSC1) and loss of immunoreactivity for tuberin (TSC2).
Examination of LAM tissues shows the expression of cleaved β-catenin products and MMP7 consistent with a model that tuberin-deficient cells acquire invasive properties through a β-catenin-dependent mechanism, which may underlie the development of LAM.
Loss of heterozygosity analysis demonstrated that not only lymphangioleiomyomatosis and renal angiomyolipoma but also the uterine angiosarcoma had loss of heterozygosity on TSC2.
Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleiomyomatosis.
A TSC2 loss or mutation leads to disruption of the tuberin-hamartin heteromer and dysregulation of S6K1 activation leading to aberrant cell proliferation seen in LAM disease.
In vitro, CCL2 or MCP-1 induced selective migration of cells, showing loss of heterozygosity of TSC2 from a heterogeneous population of cells grown from explanted LAM lungs.
The TSC1/TSC2 protein-related signaling pathways are involved in the pathogenesis and may provide novel therapeutic targets for lymphangioleiomyomatosis and diseases associated with TSC1 / TSC2 dysfunction.
These findings suggest a higher rate of LAM in TSC1 than previously recognised, as well as a fundamental difference in CT presentation between TSC1 and TSC2.
The formulation's ability to penetrate through bronchial epithelial layer was evaluated using a Calu-3 cell model, while its ability to interfere with the LAM intracellular cascade was evaluated using Mouse Embryonic fibroblast (MEF) cells deficient for the tuberous sclerosis complex 2 (TSC2) and compared with rapamycin solution.
Cumulatively, data presented here support the hypothesis that interactions between tuberin, ERalpha, and CaM may play a critical role in the pathology of LAM disease.
In HBV-D treated patients the dominant resistance mutation was rtL80V (31.4%) and rtM204I (60%) in LAM+ADV group while LAM-treated patients showed a preference of rtM204V (51.9%).
These data demonstrate that TSC2 controls cell migration through its N-terminus by associating with TSC1 and regulating RhoA activity, suggesting that TSC2 may play a critical role in modulating cell migration and invasiveness, which contributes to the pathobiology of LAM.
The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is hyperactivated in a variety of cancers and disorders, including lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC), which are characterized by mutations in tumor suppressors TSC1 or TSC2.