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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/221200
From stem cells to cancer: novel methods for tracking clonal behavior and tumour heterogeneity
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[eng] Hematopoietic stem and progenitor cells serve as a cornerstone of tissue homeostasis, enabling the generation of diverse blood cell types and immune responses. However, aberrations in their clonal dynamics and differentiation trajectories underpin a range of pathological conditions, including hematological malignancies, cardiovascular diseases, and tumor progression. This thesis employs advanced single-cell and lineage-tracing methodologies to dissect the cellular and molecular mechanisms governing stem cell behavior, differentiation, and functional diversity across disease contexts. In the first study, we elucidate the role of the cellular state of origin in dictating leukemic phenotypes. Using clonal tracing in mouse models, we demonstrate that low fitness stem cells, typically outcompeted during normal hematopoiesis, gain a competitive advantage following mutations in Dnmt3a-R878H or Npm1c. These mutations not only amplify specific clones but also reprogram their differentiation trajectories, underscoring the role of clonal "reaction norms" in cancer heterogeneity. The second study presents EPI-clone, a transgene-free lineage-tracing framework leveraging somatic epimutations to resolve clonal dynamics at single-cell resolution. Applied to murine and human hematopoiesis, EPI-clone reveals that age-related myeloid bias arises from a restricted pool of expanded clones, while many functionally young-like clones persist. In humans, we identify a spectrum of age-related clonal expansions, both with and without driver mutations, establishing a continuum of clonal hematopoiesis in ageing. The third study investigates the role of hematopoietic stem cells (HSCs) in emergency hematopoiesis (EH) following myocardial infarction (MI). By profiling human bone marrow from cardiac surgery patients, we uncover transcriptional and functional shifts in HSCs that promote pro-inflammatory myelopoiesis, contributing to impaired cardiac repair. Therapeutically, enforcing HSC quiescence via 4-oxo-retinoic acid mitigates inflammatory myelopoiesis, preserving cardiac function post-MI and providing a potential strategy for modulating excessive immune responses. Finally, the fourth study explores neutrophil development and its implications for cancer progression. We identify the cationic amino acid transporter Slc7a7 as a critical regulator of neutrophil maturation and function. Loss of Slc7a7 disrupts differentiation trajectories, reduces pro-inflammatory responses, and diminishes neutrophil extracellular trap (NET) formation. Remarkably, Slc7a7 deficiency delays tumor progression in a melanoma model, highlighting amino acid metabolism as a promising therapeutic target to modulate neutrophil responses in inflammatory diseases and cancer. Collectively, this thesis provides a comprehensive exploration of stem and progenitor cell biology across diverse pathological contexts, offering novel insights into clonal dynamics, differentiation plasticity, and therapeutic interventions. These findings advance our understanding of the cellular hierarchies and molecular pathways that underpin disease progression, with implications for targeted therapies in cancer, cardiovascular disease, and immune dysregulation.
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SINGH, Indranil. From stem cells to cancer: novel methods for tracking clonal behavior and tumour heterogeneity. [consulta: 26 de novembre de 2025]. [Disponible a: https://hdl.handle.net/2445/221200]