Journal
CANCER DISCOVERY
Volume 9, Issue 10, Pages 1406-1421Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-0138
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Funding
- DFG Research Fellowship [HA 7723/1-1]
- Innovation Fund of the Austrian Academy of Sciences [IF_2015_36]
- Austrian Science Fund (FWF) Special Research Programme [FWF SFB F 6102-B21]
- EMBO Long-Term Fellowship [ALTF 241-2017]
- New Frontiers Group award of the Austrian Academy of Sciences
- European Research Council (ERC) Starting Grant (European Union's Horizon 2020 Research and Innovation Programme) [679146]
- St. Anna Kinderkrebsforschung
- Histiocytosis Association
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Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children, It occupies a hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity. we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analyzed biopsies using IHC. and we defined an epigenomic and generegulatory basis of the different LCH-cell subsets by chromatin-accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions. SIGNIFICANCE: This study sketches a molecular portrait of LCH lesions by combining single-cell transcriptomics with epigenome profiling. We uncovered extensive cellular heterogeneity, explained in part by an intrinsic developmental hierarchy of LCH cells. Our findings provide new insights and hypotheses for advancing LCH research and a starting point for personalizing therapy.
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