An unexpected developmental hierarchy in a rare disease affecting young children

Langerhans cell histiocytosis (LCH) is a rare disease affecting primarily young children. While LCH may heal by itself without treatment in some patients, others require intensive chemotherapy and suffer from long-term consequences, or may even succumb to the disease. The reasons for these differences in disease severity are poorly understood. In a new study published in Cancer Discovery, researchers from the St. Anna Children’s Cancer Research Institute (CCRI) and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences revealed important insights into the cellular heterogeneity and molecular mechanisms underlying LCH.

Langerhans cell histiocytosis (LCH) is a very unusual disease: Often classified as a cancer because of uncontrolled cell growth in different parts of the body, it also has features of an autoimmune disease, as LCH lesions attract immune cells and show characteristic tissue inflammation. LCH is clinically variable and often difficult to diagnose. Skin involvement in babies with LCH can look like a nappy rash, whereas bone involvement can be mistaken as sarcoma in an X-ray picture. In its most aggressive form, LCH can present as leukemia-like disease and lead to organ failure. These diverse manifestations and the enormous clinical heterogeneity of LCH continue to puzzle medical doctors and scientists around the world.

Studying LCH lesions under the microscope, Caroline Hutter - a pediatric oncologist at St. Anna Children's Hospital, principal investigator at CCRI and co-lead investigator of this study - observed striking heterogeneity among LCH cells. To investigate this diversity in full molecular detail, she assembled an interdisciplinary team including experimental and computational researchers from CCRI and CeMM, as well as medical doctors from St. Anna Children's Hospital and Vienna General Hospital. Her aim was to answer two fundamental questions: What are the mechanisms behind LCH, and how can we improve treatment of children affected by this disease?

Utilizing state-of-the-art technology in the laboratory of co-lead investigator Christoph Bock (CeMM), LCH lesions were analyzed for their molecular composition at single-cell resolution. Spearheaded by one computational postdoc, Florian Halbritter (now at CCRI), and one wet-lab postdoc, Matthias Farlik (now at Medical University of Vienna), the team analyzed the molecular profiles of LCH lesions and developed a comprehensive map of cellular heterogeneity in LCH.

In this molecular map of LCH, the team identified multiple LCH cell subtypes. One of these subtypes comprised actively dividing cells, which appear to give rise to the other LCH cell subtypes. In further experiments, the team unraveled the molecular pathways that are active in different branches of this unexpected developmental hierarchy, which corroborated an interplay of developmental, immunological, and oncogenic mechanisms in LCH.

The study is a significant step forward in the understanding of this enigmatic disease. In future, these finding may help devise better ways of distinguishing severe from less severe disease cases, and they may even open up new treatment possibilities.