SUMMARY

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.

SIGNIFICANCE

Present study identified a novel population of LAM^CORE cells, which is likely originated from uterine neural crest; identified novel LAM cell-specific secretome proteins that hold promise as potential biomarkers and therapeutic targets. Advancing the understanding of LAM pathogenesis and metastasis model may yield broader insights into the biology of cancer.

Research laboratories contributed to this work

Publication

American Journal of Respiratory and Critical Care Medicine

PubMed

bioRxiv

Query function

LAM scRNA-seq gene query

LAM scRNA-seq cell query

Characterization of LAM^CORE

Data Availability

All sequencing data from the present study has been deposited to GEO (https://www.ncbi.nlm.nih.gov/geo/). R code used for data analysis is available at Github - Xu Lab.

• scRNA-seq data (Reyfman et al., 2018)of six female human lungs (GSE122960).
• scRNA-seq data from normal mouse uterus (GSE118180).
• RNA-seq data from Illumina’s Human BodyMap 2.0 was downloaded from Gene Expression Omnibus (GSE30611).
• scRNA-seq and snRNA-seq from 10x Chromium platform on four lung explants from LAM patients undergoing lung transplantation. (GSE135851).