Identification of the lymphangioleiomyomatosis cell and its uterine origin

Abstract

Lymphangioleiomyomatosis (LAM) is a metastasizing neoplasm of reproductive age women that causes cystic lung remodeling and progressive respiratory failure. The source of LAM cells that invade the lung and the reasons that LAM targets women have remained elusive. We employed single cell and single nuclei RNA sequencing on LAM lesions within explanted LAM lungs, known to contain smooth muscle like cells bearing mTOR activating mutations in TSC1 or TSC2, and identified a unique population of cells that were readily distinguished from those of endogenous lung cells. LAM CORE cells shared closest transcriptomic similarity to normal uterus and neural crest. Immunofluorescence microscopy demonstrated the expression of LAM CORE cell signature genes within LAM lesions in both lung and uterus. Serum aptamer proteomics and ELISA identified biomarkers predicted to be secreted by LAM CORE cells. Single cell transcriptomics strongly supports a uterine neural crest origin of LAM CORE cells; providing insights into disease pathogenesis and informing future treatment strategies for LAM.

Lymphangioleiomyomatosis: a clinical review

“…These include alternative blood-based biomarkers [73] and improved use of CT imaging technology to determine progressive disease in those with normal spirometry [74,75]. Recent studies have identified that that LAM cells probably originate in the uterus and specific proteins associated with this may be novel biomarkers [76]. These continued advances in understanding the molecular pathogenesis will potentially identify better therapeutic options and reveal more robust clinically meaningful biomarkers.…”

Three-dimensional drug screen identifies HDAC inhibitors as therapeutic agents in mTORC1-driven lymphangioleiomyomatosis

“…1J, right panel). We next examined the overlap of these DEGs with a recently published LAM gene signature derived from single cell RNA-seq profiling of primary lesions (24). We observed that both DEG lists overlap substantially (65.8% of the total 760 LAM genes) and share both common and distinct genes with the LAM gene signature (Fig.…”

“…S1I-J). Both DEG lists ranked "extracellular matrix organization" as most highly enriched, which is also the top enriched term in a primary LAM lesion gene signature list (24). The DEGs distinguishing genotype were also enriched in many terms related to development, similar to primary LAM lesions (24).…”