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Heterogeneity and Cancer-Related Features in Lymphangioleiomyomatosis Cells and Tissue.

ABSTRACT: Lymphangioleiomyomatosis (LAM) is a rare, low-grade metastasizing disease characterized by cystic lung destruction. LAM can exhibit extensive heterogeneity at the molecular, cellular, and tissue levels. However, the molecular similarities and differences among LAM cells and tissue, and their connection to cancer features are not fully understood. By integrating complementary gene and protein LAM signatures, and single-cell and bulk tissue transcriptome profiles, we show sources of disease heterogeneity, and how they correspond to cancer molecular portraits. Subsets of LAM diseased cells differ with respect to gene expression profiles related to hormones, metabolism, proliferation, and stemness. Phenotypic diseased cell differences are identified by evaluating lumican (LUM) proteoglycan and YB1 transcription factor expression in LAM lung lesions. The RUNX1 and IRF1 transcription factors are predicted to regulate LAM cell signatures, and both regulators are expressed in LAM lung lesions, with differences between spindle-like and epithelioid LAM cells. The cancer single-cell transcriptome profiles most similar to those of LAM cells include a breast cancer mesenchymal cell model and lines derived from pleural mesotheliomas. Heterogeneity is also found in LAM lung tissue, where it is mainly determined by immune system factors. Variable expression of the multifunctional innate immunity protein LCN2 is linked to disease heterogeneity. This protein is found to be more abundant in blood plasma from LAM patients than from healthy women. IMPLICATIONS: This study identifies LAM molecular and cellular features, master regulators, cancer similarities, and potential causes of disease heterogeneity.

SUBMITTER: Espin R

PROVIDER: S-EPMC8568632 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Heterogeneity and Cancer-Related Features in Lymphangioleiomyomatosis Cells and Tissue.

Espín Roderic R Baiges Alexandra A Blommaert Eline E Herranz Carmen C Roman Antonio A Saez Berta B Ancochea Julio J Valenzuela Claudia C Ussetti Piedad P Laporta Rosalía R Rodríguez-Portal José A JA van Moorsel Coline H M CHM van der Vis Joanne J JJ Quanjel Marian J R MJR Villar-Piqué Anna A Diaz-Lucena Daniela D Llorens Franc F Casanova Álvaro Á Molina-Molina María M Plass Mireya M Mateo Francesca F Moss Joel J Pujana Miquel Angel MA

Molecular cancer research : MCR 20210726 11

Lymphangioleiomyomatosis (LAM) is a rare, low-grade metastasizing disease characterized by cystic lung destruction. LAM can exhibit extensive heterogeneity at the molecular, cellular, and tissue levels. However, the molecular similarities and differences among LAM cells and tissue, and their connection to cancer features are not fully understood. By integrating complementary gene and protein LAM signatures, and single-cell and bulk tissue transcriptome profiles, we show sources of disease hetero ...[more]

PMID: 34312290

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Project description:Rationale: Lymphangioleiomyomatosis (LAM) is a rare disease associated with cystic destruction of the pulmonary parenchyma and chronic respiratory failure, and there are trials underway to determine if early intervention can prevent disease progression. An imaging technique that is sensitive to early regional disease would therefore be valuable for patient care and clinical trials.Objectives: We postulated that hyperpolarized 129Xe MRI would be sensitive to ventilation abnormalities and alveolar airspace dilation in patients with mild LAM disease and normal pulmonary function and that 129Xe MRI would reveal important features of cyst ventilation.Methods: 129Xe ventilation and diffusion-weighted MR images were acquired in 22 patients with LAM during two breath-holds of hyperpolarized 129Xe. 129Xe ventilation defect percentage (VDP; percentage of voxels <60% of the mean whole-lung 129Xe MRI signal) and apparent diffusion coefficient (ADC), a measure of alveolar airspace size, were quantified and compared with pulmonary function test parameters with Spearman statistics. Sixteen patients with LAM had a recent, clinical chest computed tomography (CT) scan available, and cyst ventilation was assessed by thresholding cysts on the CT images and registration to the 129Xe ventilation images.Results: Ventilation deficits were observed in all patients with LAM, including those with normal pulmonary function and few cysts, and the mean VDP was 19.2% (95% confidence interval [CI], 14.8-23.5%). 129Xe VDP was strongly correlated with forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio (r = -0.51, P = 0.02) and diffusing capacity of the lung for carbon monoxide (DlCO) (r = -0.60, P = 0.009) but not with FEV1 (r = -0.33, P = 0.13), likely because of the sensitivity of 129Xe MRI to mild LAM disease in patients with normal FEV1. The mean ADC was 0.048 cm2/s (95% CI, 0.042-0.053 cm2/s). In many cases, ADC was elevated relative to previously reported values in adults, and ADC was correlated with FEV1, FEV1/FVC ratio, and DlCO (P ≤ 0.02 for all). Co-registered 129Xe MRI and CT imaging revealed considerable ventilation heterogeneity within individual patients with LAM and across patients with similarly sized cysts.Conclusions: 129Xe MRI provides a means to assess the complex regional ventilation and alveolar airspace size changes of LAM with high sensitivity and may be a clinically useful future tool for screening, managing patients, and measuring treatment efficacy.

Dataset Information

Heterogeneity and Cancer-Related Features in Lymphangioleiomyomatosis Cells and Tissue.

Publications

Heterogeneity and Cancer-Related Features in Lymphangioleiomyomatosis Cells and Tissue.

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