Project Details
Projekt
Genetic and non-genetic determinants of brain cancer-associated clonal myeloid cell dynamics and plasticity
Applicants
Dr. Ilon Liu; Dr. Leif Ludwig
Subject Area
Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 500300783
Myeloid cells of the central nervous system (CNS) including microglia have been implicated as key contributors to brain tumor evolution, therapy resistance, as well as cancer therapy-induced neurotoxicity. Despite increasing evidence of their diversity and central function in homeostasis and across different brain pathologies, the clonal dynamics and evolutionary trajectories of CNS myeloid cells in vivo in the human brain remain largely enigmatic due to so far technical limitations in clonal tracing and leveraging archival human cohorts. Thus, it remains to be elucidated to what extent brain tumor-associated myeloid cells i) present clonally expanded populations, ii) are plastic, i.e., are capable of transitioning into different cellular states over time and in response to therapy, and iii) how both non-genetic and genetic mechanisms regulate these states and plasticity. The overarching goal of this proposal is to attain an in-depth understanding of CNS myeloid immune cells’ clonality, their dynamics, and their underlying genetic and non-genetic modulators in the context of brain cancer pathobiology and cancer therapy-induced neurotoxicity. Specifically, we will utilize somatic mitochondrial DNA mutations as naturally occurring cellular barcodes resolved via single-cell multi-omics in longitudinal cohorts of glioblastoma patients before and after standard radiochemotherapy to systematically trace the clonal fates of CNS myeloid cells. Further, we will investigate the so far unexplored prevalence of clonal hematopoiesis of indeterminate potential, a prevalent condition in the ageing population, in the typical elderly glioblastoma patient, and asses its impact on glioma-associated myeloid cells as recently intimidated in Alzheimer’s disease. Together, this project will provide fundamental insights into i) the evolution and plasticity of CNS myeloid populations that crucially contribute to tumor resistance and therapy-induced neurotoxicity, and ii) how these populations are regulated by both non-genetic and genetic mechanisms. Ultimately, we envision that the proposed project will further help inform and advance much-needed therapies that specifically target myeloid cell populations responsible for tumor resistance and toxicity, which may also readily translate to other types of cancers and CNS diseases.
DFG Programme
Priority Programmes
