ENOrphanet Journal of Rare Diseases | CCL14 as a Novel Biomarker for Disease Progression in Lymphangioleiomyomatosis
Date: February 16, 2026
Classification: Frontiers
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This study, using a multi-omics approach, first reveals that CCL14 is secreted by endothelial cells within the lymphangioleiomyomatosis (LAM) microenvironment and participates in disease progression regulation. It validates CCL14 as an independent structural damage predictor biomarker distinct from VEGF-D, demonstrating significant clinical application potential.
Literature Overview
The article titled 'CCL14, identified by multi-omics approach, serves as a novel indicator of disease severity and progression in lymphangioleiomyomatosis,' published in the journal *Orphanet Journal of Rare Diseases*, reviews and summarizes the expression profile, cellular origin, functional mechanisms, and clinical phenotype associations of CCL14 in lymphangioleiomyomatosis (LAM). By integrating plasma proteomics, single-cell RNA sequencing, and clinical cohort validation, this study systematically reveals the regulatory role of CCL14 in the LAM tumor microenvironment and demonstrates its potential as a novel biomarker for disease severity and structural progression. This work provides new insights into the pathogenesis of LAM and offers a potential tool for clinical monitoring.Background Knowledge
Lymphangioleiomyomatosis (LAM) is a rare, progressive multisystem disease primarily affecting women of reproductive age, characterized by cystic lung destruction, renal angiomyolipomas (AMLs), and lymphatic system involvement. The disease is caused by mutations in the TSC1/TSC2 genes, leading to aberrant activation of the mTOR pathway and driving abnormal proliferation and migration of LAM cells. Although VEGF-D is currently the core diagnostic biomarker, it has limitations in predicting disease progression and structural damage. The tumor microenvironment (TME) plays a critical role in LAM progression, where chemokine-mediated intercellular communication influences inflammation, angiogenesis, and immune regulation. CCL14 is a CC-class chemokine reported to have dual functions in various cancers but has not been studied in LAM. This study builds on prior proteomic findings showing significantly elevated plasma CCL14 levels in LAM patients, and further explores its cellular origin, signaling pathways, and clinical significance, thereby filling a gap in the field. Using single-cell transcriptomics, the study precisely identifies the cell types expressing CCL14, and combines functional enrichment, ligand-receptor interaction analysis, and in vitro experiments to systematically dissect its underlying mechanisms. The study's focus lies in leveraging multi-omics strategies to uncover new functional biomarkers, aiming to address the clinical challenge of insufficient structural progression prediction by existing biomarkers and providing new tools for personalized management of LAM.
Research Methods and Experiments
The study first screened the chemokine CCL14, significantly upregulated in LAM patients, based on previously published plasma proteomic data. Subsequently, public and in-house lung tissue single-cell RNA sequencing (scRNA-seq) datasets—including 6 LAM patients and 5 healthy donors—were integrated. Using the Seurat pipeline, data quality control, integration, clustering, and annotation were performed to identify the cellular sources of CCL14. GO and Hallmark pathway enrichment analyses were used to explore CCL14-related functions, and CellPhoneDB was applied to analyze the ligand-receptor interaction networks mediated by CCL14. At the tissue level, immunohistochemistry (IHC) was used to validate CCL14 protein expression in LAM lesions. In vitro, human umbilical vein endothelial cells (HUVECs) were used to evaluate the effect of CCL14 on the mTOR pathway, with downstream molecules such as p-S6 detected via Western blot. In the clinical validation cohort, 53 LAM patients and 25 healthy controls were enrolled. Plasma CCL14 levels were measured using ELISA, and their associations with clinical phenotypes (e.g., AMLs, CT grading) and longitudinal disease progression (based on lung function and CT structural changes) were analyzed. Statistical analyses included Mann-Whitney U test, Spearman correlation analysis, ROC curve analysis, and Kaplan-Meier survival analysis.Key Conclusions and Insights
Research Significance and Outlook
This study systematically reveals the critical regulatory role of CCL14 in the pathogenesis of LAM, expanding our understanding of the chemokine network within the LAM tumor microenvironment and offering a new biomarker option for disease monitoring. As an endothelial cell-derived factor, CCL14 may contribute to lymphangiogenesis and vascular remodeling, thereby promoting structural destruction. Its non-overlapping nature with VEGF-D suggests that the two could be combined for more comprehensive disease assessment.
Future studies could further validate the prognostic value of CCL14 in independent multicenter cohorts and explore its potential in monitoring treatment response. Moreover, the receptors of CCL14—ACKR2, CCR3, and CCR1—could serve as potential therapeutic targets; developing antagonists or antibodies may offer new treatment strategies for LAM. Dynamic analysis at the single-cell level will also help elucidate the evolutionary trajectory of CCL14+ endothelial cell subsets and their roles at different disease stages.
Conclusion
By integrating multi-omics analysis and clinical validation, this study establishes CCL14 as a key microenvironmental regulator in lymphangioleiomyomatosis (LAM). It is found that CCL14 is primarily secreted by lymphatic and vascular endothelial cells and significantly upregulated in LAM patients, participating in cell proliferation and inflammatory responses through activation of pathways such as mTORC1. The intercellular communication network mediated by CCL14 influences immune cell recruitment and epithelial-endothelial interactions, potentially promoting lesion progression. Clinical data show that plasma CCL14 levels are significantly associated with renal angiomyolipomas and severe cystic lung lesions, and can independently predict structural disease progression, outperforming the traditional biomarker VEGF-D. This molecule reflects tissue structural damage rather than pulmonary functional decline, making it a complementary biomarker to VEGF-D for more precise disease monitoring. In summary, CCL14 not only provides new insights into the pathogenesis of LAM but also holds potential for translation into clinical tools, with future applications in risk stratification, efficacy evaluation, and targeted intervention development, advancing personalized management of LAM.
