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 LAMCORE 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.
Keywords: lymphangioleiomyomatosis, lung, single cell analysis, origin, uterus
Guo, Minzhe and Yu, Jane J. and Perl, Anne Karina and Wikenheiser-Brokamp, Kathryn A. and Riccetti, Matt and Zhang, Erik Y. and Sudha, Parvathi and Adam, Mike and Potter, Andrew and Kopras, Elizabeth J. and Giannikou, Krinio and Potter, S. Steven and Sherman, Sue and Hammes, Stephen R. and Kwiatkowski, David J. and Whitsett, Jeffrey A. and McCormack, Francis X. and Xu, Yan, Identification of the Lymphangioleiomyomatosis Cell and Its Uterine Origin (September 30, 2019). Available at SSRN: https://ssrn.com/abstract=3461777 or http://dx.doi.org/10.2139/ssrn.3461777
This version of the paper has not been formally peer reviewed.
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