Decoding the lymphangioleiomyomatosis niche microenvironment via integrative analysis of single cell multiomics and spatial transcriptomics
11 affiliations
- 1The Perinatal Institute and Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- 2Department of Plant and Microbial Biology, University of California, Berkeley, CA, USA
- 3Contributed equally to the work as first authors
- 4Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA
- 5Institute of Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA
- 6Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati School of Medicine, Cincinnati, OH, USA
- 7Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
- 8Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- 9Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
- 10Department of Pathology and Laboratory Medicine, University of Cincinnati School of Medicine, Cincinnati, OH, USA
- 11Department of Biomedical Informatics, University of Cincinnati School of Medicine, Cincinnati, OH, USA
Abstract
Lymphangioleiomyomatosis (LAM) is a rare, destructive lung disease caused by mutations in tuberous sclerosis complex 1 (TSC1) or TSC2, leading to mammalian target of rapamycin complex 1 (mTORC1) hyperactivation. While mTOR inhibitor sirolimus, the only US Food and Drug Administration approved drug for this disease, stabilises lung function in most LAM patients, the drug does not eliminate LAM cells, underscoring a critical gap in our understanding of the tumour microenvironment and cellular heterogeneity that drive disease progression. This study provides the first comprehensive multiomics atlas of the human LAM niche, integrating single-cell/single-nucleus RNA-sequencing, single-nucleus ATAC-sequencing, and spatial transcriptomics to deconvolute its complex architecture. We elucidate LAM cellular heterogeneity by identifying three distinct subtypes: the canonical, uterine smooth muscle-like, mTORC1-hyperactive LAMCORE1; a novel, fibroblast-like LAMCORE2 subtype with potent extracellular matrix (ECM) remodelling activity; and LAMCORE3, a substate of LAMCORE1 that shares LAM and myogenic signatures, but is characterised by lower transcriptional activity and specific functional enrichment in protein translation. Our analysis reveals the transcriptomic heterogeneity of the LAM subtypes, orchestrated by distinct transcriptional drivers and networks. Furthermore, we uncover spatially resolved LAM-associated fibroblast (LAF) states, LAF-seed and LAF-niche, that coordinate transforming growth factor-β signalling, ECM deposition and remodelling, and niche expansion. Spatial mapping uncovers a structured ecosystem where LAMCORE1 cells form a central core enmeshed with the lymphatic endothelium, which is surrounded by LAFs, LAMCORE2 cells, and reprogrammed immune and epithelial cells. Findings were validated through multimodal imaging technologies. Present work advances the field by providing the first high-resolution blueprint of the LAM niche microenvironment, revealing novel cell states and crosstalk that identify promising novel therapeutic targets.
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BibTeX
@article{chen2026decoding,
title = {{Decoding the lymphangioleiomyomatosis niche microenvironment via integrative analysis of single cell multiomics and spatial transcriptomics}},
author = {Ken Chen and Shuyang Zhao and Minzhe Guo and Hasan Reza and Andrew Wagner and Adnan Cihan Cakar and Cheng Jiang and Erik Zhang and Jenna Green and Emily P. Martin and Grace A. Wikenheiser and Kathryn A. Wikenheiser-Brokamp and Anne Karina Perl and Debora Sinner and Jane J. Yu and Yan Xu},
journal = {The European Respiratory Journal},
year = {2026},
month = nov,
doi = {10.1183/13993003.02049-2025},
url = {https://doi.org/10.1183/13993003.02049-2025},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Decoding the lymphangioleiomyomatosis niche microenvironment via integrative analysis of single cell multiomics and spatial transcriptomics
AU - Ken Chen
AU - Shuyang Zhao
AU - Minzhe Guo
AU - Hasan Reza
AU - Andrew Wagner
AU - Adnan Cihan Cakar
AU - Cheng Jiang
AU - Erik Zhang
AU - Jenna Green
AU - Emily P. Martin
AU - Grace A. Wikenheiser
AU - Kathryn A. Wikenheiser-Brokamp
AU - Anne Karina Perl
AU - Debora Sinner
AU - Jane J. Yu
AU - Yan Xu
PY - 2026
DA - 2026/11/05
JO - The European Respiratory Journal
DO - 10.1183/13993003.02049-2025
UR - https://doi.org/10.1183/13993003.02049-2025
AB - Lymphangioleiomyomatosis (LAM) is a rare, destructive lung disease caused by mutations in tuberous sclerosis complex 1 (TSC1) or TSC2, leading to mammalian target of rapamycin complex 1 (mTORC1) hyperactivation. While mTOR inhibitor sirolimus, the only US Food and Drug Administration approved drug for this disease, stabilises lung function in most LAM patients, the drug does not eliminate LAM cells, underscoring a critical gap in our understanding of the tumour microenvironment and cellular heterogeneity that drive disease progression. This study provides the first comprehensive multiomics atlas of the human LAM niche, integrating single-cell/single-nucleus RNA-sequencing, single-nucleus ATAC-sequencing, and spatial transcriptomics to deconvolute its complex architecture. We elucidate LAM cellular heterogeneity by identifying three distinct subtypes: the canonical, uterine smooth muscle-like, mTORC1-hyperactive LAMCORE1; a novel, fibroblast-like LAMCORE2 subtype with potent extracellular matrix (ECM) remodelling activity; and LAMCORE3, a substate of LAMCORE1 that shares LAM and myogenic signatures, but is characterised by lower transcriptional activity and specific functional enrichment in protein translation. Our analysis reveals the transcriptomic heterogeneity of the LAM subtypes, orchestrated by distinct transcriptional drivers and networks. Furthermore, we uncover spatially resolved LAM-associated fibroblast (LAF) states, LAF-seed and LAF-niche, that coordinate transforming growth factor-β signalling, ECM deposition and remodelling, and niche expansion. Spatial mapping uncovers a structured ecosystem where LAMCORE1 cells form a central core enmeshed with the lymphatic endothelium, which is surrounded by LAFs, LAMCORE2 cells, and reprogrammed immune and epithelial cells. Findings were validated through multimodal imaging technologies. Present work advances the field by providing the first high-resolution blueprint of the LAM niche microenvironment, revealing novel cell states and crosstalk that identify promising novel therapeutic targets.
SN - 0903-1936
SN - 1399-3003
ER -