Project Details
Projekt
Neuroblastoma as pediatric tumor model: in vivo mechanical niches in zebrafish and patients
Subject Area
Medical Physics, Biomedical Technology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 513752256
Neuroblastoma is a difficult-to-treat malignant childhood cancer that originates in the sympathetic nervous system. High-risk tumors with unfavorable prognosis are extremely aggressive and already metastasize to bone, bone marrow, and liver at the time of diagnosis, whereas low-risk neuroblastomas usually regress spontaneously or differentiate into benign forms. Previously, communication between tumor cells and surrounding tissues, including the extracellular matrix (ECM), was thought to rely solely on biochemical signaling. However, recent studies have shown that the mechanical properties of the tumor environment can directly activate cell-internal mechanotransduction pathways such as the YAP/TAZ/Hippo signaling pathway. This interaction, which has been poorly studied to date, may influence tumor progression and response to therapy and thus play an important role in disease progression. We hypothesize that the biophysical properties of the mechanical tumor niche contribute to progression, differentiation, metastasis, and/or resistance to therapy in neuroblastoma. Project B01 will characterize the mechanical properties and corresponding mechanotransduction pathways in primary and relapsed neuroblastoma and its metastases in the context of their tissue environment in patients and in zebrafish models of metastatic neuroblastoma. To this end, we will (i) use atomic force microscopy (AFM) to quantify the viscoelasticity of single tumor cells from zebrafish tumors and human cell lines (with A01, A03), (ii) perform cell and nuclear shape analysis (CeNuS, A03) of single cells, to determine mobility states (jamming transition) in histological sections of human tumor samples or whole zebrafish and live cells in transplanted zebrafish embryos, and (iii) quantify viscoelasticity of primary and secondary tumors by micro-MR elastography (µMRE) in transgenic zebrafish (with C02) and after vital decellularization of their extracellular matrix (with B03). B01 will further investigate the potential of clinical MRE imaging to assess neuroblastoma in patients (with C01). The data collected will be compared with data from single cell transcriptome analysis to identify important mechanotransduction pathways and metabolic changes (with A02). Data from project B01 will provide the research unit with unique complementary data collected in a library of tumor mechanobiology data across length scales and dynamic ranges from zebrafish to patients (C03) addressing the pediatric cancer niche and synergistically complement the efforts undertaken in B02, C01 and C02 in larger in-vivo tumor models and patients addressing predamaged, adult tumor niches. Our long-term goal is an in-depth understanding of the mechanical cancer niche and its role in metastatic neuroblastoma as a starting point and new avenue towards future diagnostic and therapeutic exploitation.
DFG Programme
Research Units
