Research > Focus A > Work Packages A04
Summary
In this project, we aim to understand how tumor subpopulations influence the transcriptional states of tumor associated microglia (TAM) in malignant astrocytomas harboring isocitrate dehydrogenase (IDH) mutations. Dynamic and complex interactions occur between gliomas and TAM in the tumor microenvironment and these interactions are further compounded by tumor heterogeneity. Specific interactions between tumor subpopulations and TAM states remain unresolved. An understanding of how specific alterations in tumors impact the TAM microenvironment will be important for development of novel therapeutic options.
Task 1
Evaluate the impact of molecular drivers of tumor and TAM interactions on tumor burden in intracranial models of grade 4 astrocytoma
Steps / Workflow
- Generate cell lines with tumor-specific loss or gain of candidate receptor/ligands
- Intracranial implantation of the created cell lines to ascertain the effect of the gene on tumor growth
- Imaging the tumorassociated microglia (TAM) using light-sheet fluorescence microscopy to determine quantity and spatial localization
Task 2
Determine the intratumoral TAM heterogeneity associated with tumor specific ligands
Steps / Workflow
- Single cell RNA-seq (scRNA-seq) from tumors implanted with candidate cell lines from Task 1
- Data analysis to determine TAM diversity in tumors generated from candidate cell lines
- Generate inducible lines of select candidates to test TAM states in vivo
- scRNA-seq from the inducible lines to determine TAM state reversion in vivo
Task 3
Identify molecular interactions between TAMs and TME in recurrent astrocytomas
Steps / Workflow
- Single-nucleus RNA-seq of matched primary and recurrent astrocytomas
- Data analysis to determine transcriptional changes associated with recurrence
- Data analysis to determine receptor-ligand interactions between cells derived from the tumor and the tumor microenvironment (TME)
Previous Funding period
PRINCIPLE INVESTIGATOR
TURCAN, SEVIN, PH.D
Junior Research Group Leader
University Hospital Heidelberg, Department of Neurology, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany