Tracing Heterogeneity in T-cell Malignancies in Time and Space: Unveiling phenotypic plasticity and migration dynamics through single-cell multi-omics

Our bodies renew some organs frequently, such as the intestines and skin, while others, like the brain and heart, rarely renew. This renewal process involves cell division, during which mutations can occur. While many mutations are harmless or corrected by cells, some mutations can disrupt cell functions and lead to cancer. These mutations, unique to each cell, act as a "barcode," allowing researchers to trace cell lineage and study cancer development using family tree methods. Advances in DNA analysis have improved the precision of this approach, enabling a deeper understanding of cellular mutations and their consequences.

This thesis employs the family tree principle to study T-cell leukemia and lymphoma, two types of immune system cancers. Healthy T-cells develop through a stepwise maturation process, enabling them to recognize foreign substances and activate the immune system. In T-cell leukemia and lymphoma, DNA mutations disrupt this maturation, causing cells to remain immature. These faulty cells multiply, leading to leukemia when accumulated in the blood and bone marrow or lymphoma when found in the lymph nodes. In the Netherlands, 20 children are diagnosed annually with these cancers, and while 80% recover through intensive chemotherapy, the treatment is lengthy and burdensome. This research seeks to develop more effective, less toxic treatments.

Chapter 2 explores the varying characteristics of tumor cells within a single patient, corresponding to different stages of T-cell maturation. Using family tree analysis, the study revealed that leukemia cells can exhibit characteristics of both normal and reverse T-cell development. This finding challenges the previous understanding that leukemia cells uniformly display immature features. Moreover, ongoing T-cell maturation within leukemia cells was demonstrated for the first time, offering insights into cancer progression.

Chapter 3 compares healthy developing T-cells with leukemia cells, identifying differences in surface characteristics and internal processes. At relapse, leukemia cells exhibit stem cell-like properties, such as slower division and adaptability, making them more resistant to therapies targeting rapidly dividing cells. The study's dataset is publicly available to support further research and hypothesis testing.

Chapter 4 focuses on T-cell lymphoma, which primarily accumulates in the lymph nodes but often spreads to multiple organs, such as the bone marrow and brain. Family tree analysis revealed that lymphoma cells continuously migrate between organs from the onset of the disease, contrasting with other cancers that typically spread later.

The findings in this thesis enhance our understanding of T-cell leukemia and lymphoma, their progression, and their distinct characteristics. This knowledge provides a foundation for developing innovative therapies, such as immunotherapy, to target cells with specific features. These advancements aim to improve treatment efficacy while reducing the burden and side effects for patients.