Identifying mechanisms of cell-cell communication of neural precursor cells with rhabdoid tumor cells via PDGF-AA

• Applicant: Professor Dr. Kornelius Kerl
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440839161

Atypical teratoid rhabdoid tumors (AT/RT) are aggressive embryonic brain tumors mostly occurring in infants. AT/RT are characterized by biallelic alterations of the SMARCB1 gene. To elucidate mechanisms of AT/RT development, the applicant has established conditional murine AT/RT model systems. Whether and to what extent a specific tumor microenvironment (TME) is essential for the transformation and proliferation of AT/RT cells has not yet been investigated.In preliminary work the applicant has shown that murine as well as human AT/RT are characterized by infiltrating neural precursor cells. PDGF-AA and TGFA were identified as interesting candidates in the crosstalk of neural precursor cells and AT/RT cells.In this project the applicant therefore hypothesizes that a crosstalk of neural precursor cells and AT/RT cells via PDGF-AA and TGFA is essential for AT/RT proliferation. In detail, we propose that PDGF-AA secreted by neural precursor cells stimulates the proliferation, migration and vascularization of AT/RT cells, and that AT/RT cells via TGFA attract neural precursor cells and keep these cells in a stem cell-like state.Aim 1 assesses if blockade of PDGF receptor (PDGFR) signaling inhibits proliferation, migration and vascularization of AT/RT. In Aim 2, the functional effects of TGFA on neural precursor cells will be elucidated in vitro: First, the impact of TGFA on cell migration of neural precursor cells will be analyzed. Second, mechanisms by which AT/RT cells keep neural precursor cells in a stem cell-like state will be elucidated.Aim 3 investigates whether blockade of PDGFR- and TGFA-induced signaling is a promising option for targeted therapy of AT/RT in a preclinical prerequisites for an innovative target-directed therapy of AT/RT by inhibition of the PDGFR-TGFA signaling axis.

• DFG Programme: Research Grants