Lymphangioleiomyomatosis: a metastatic lung disease

Abstract

Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, caused by somatic mutations in the TSC1 or TSC2 genes, and driven by estrogen. Similar to many cancers, it is metastatic, primarily to the lung. Despite its monogenetic nature, like many cancers, LAM is a heterogeneous disease. The cellular constituents of LAM are very diverse, including mesenchymal, epithelial, endothelial, and immune cells. LAM is characterized by dysregulation of many cell signaling pathways, distinct populations of LAM cells, and a rich microenvironment, in which the immune system appears to play an important role. This review delineates the heterogeneity of LAM and focuses on the metastatic features of LAM, the deregulated signaling mechanisms and the tumor microenvironment. Understanding the tumor-host interaction in LAM may provide insights into the development of new therapeutic strategies, which could be combinatorial or superlative to Sirolimus, the current U.S. Food and Drug Administration-approved treatment.

Keywords: TSC; lung; lymphangioleiomyomatosis; mTOR; rare disease.

Graphical abstract

Figure 1.

LAM is a disease with a complex interplay of mTORC1, estrogen, and Wnt/β-catenin signaling. LAM occurs due to somatic loss-of-function mutation of tumor suppressors TSC1 or TSC2, negative regulators of the mechanistic target of rapamycin complex 1 (mTORC1). Consequently, mTORC1, a key controller of cell growth and metabolism, is inappropriately activated. Inhibitors of mTORC1 prevent LAM disease progression but are not curative. In addition, LAM cells have high expression levels of estrogen receptor (ERα) on their surface, and LAM is an estrogen-sensitive disease. Estrogen-stimulated proliferation of human TSC2-null AML cells activates both genomic (c-myc, MYH10 transcription) and nongenomic (ERK activation) pathways, leading to LAM phenotype. Estrogenic and ligand-independent activation of ERα specifically depends on mTORC1 signaling. mTORC1 activation leads to synergistic activation of ERα and upregulation of Wnt, FGF, SHH, and TGFβ signaling leading to cystic phenotype of LAM. AML, angiomyolipoma; LAM, lymphangioleiomyomatosis; mTORC1, mechanistic target of rapamycin complex 1; TSC, tuberous sclerosis complex.

Figure 2.

Molecular markers of LAM. LAM is a heterogeneous disease. The potential molecular markers of LAM mainly include LAM^p signature (a curated list of 67 proteins from single-cell LAM lesion study) and LAM^core signature (transcriptional signature of LAM single-cell RNA sequencing from four patients with LAM). Although LAM^p and LAM^core signatures overlap significantly, molecular differences remain. Within LAM^core signature, quantification of gene signature resulted in the two groups—LAM core^high and LAM core^low and are associated with different physiological functions. ECM, extracellular matrix; ER, estrogen receptor; LAM, lymphangioleiomyomatosis; PR, progesterone receptor; MIAA, 1-methyl-4-imidazole acetic acid.

Figure 3.

LAM microenvironment. LAM “nest of cells” secrete proteases including cathepsins and matrix metalloproteinases (MMPs), which degrade the extracellular matrix of lungs. In addition, LAM “nest of cells” exhibit increased expression of VEGF-D, promote the invasion of lung tissue by LAM cells, and lead to deterioration of lung functions. In addition, the proteins in the secretome of LAM “nest of cells” lead to alveolar reepithelization and ECM reorganization, lymphatic and blood vessel blockage and airway obstruction, and cause progressive loss of alveolar structure, leading to LAM pathology. ECM, extracellular matrix; LAM, lymphangioleiomyomatosis; VEGF, vascular endothelial growth factor.