The bone marrow is among the most common sites of distant metastasis in patients with high-risk neuroblastoma. Small tumor cell populations can persist in this environment after treatment and induce relapse. Therapy resistance of these residual tumor cells remains a major obstacle to cure and most neuroblastoma patients die of their metastases. We hypothesize that a detailed understanding of the molecular mechanisms regulating interactions of metastasized neuroblastoma cells with the bone marrow niche is imperative to elucidate and subsequently diagnostically and therapeutically exploit forces driving metastasis, therapy resistance and relapse. Project C03 will combine single-cell multi-omics with spatially-resolved omics technologies in longitudinal patient samples derived from the HR-NBL2/SIOPEN clinical trial, and functional assays in cell culture and innovative 3D BM-on-chip assays to study the molecular, cellular and immunological basis of neuroblastoma metastasis to the bone marrow. More specifically, we will use single-cell proteo-genomics of (i) paired primary and metastasized neuroblastoma cells to identify cell-intrinsic mediators of bone marrow metastasis (Task 1) and (ii) the microenvironment in interregional bone marrow samples to identify cell-extrinsic mediators of bone marrow metastasis (Task 2). The transcriptomic surroundings of micro-metastases in bone marrow biopsies will also be mapped using spatially-resolved transcriptomics (Task 3). Novel mediators of neuroblastoma cell homing to bone marrow and expansion identified in Tasks 1-3 will be functionally validated for their role in treatment response using sophisticated preclinical 3D models (Task 4). In a final clinical-translational approach, we will transfer selected predictive biomarkers to more robust diagnostic assays suitable for clinical routine application (Task 5). Project C03 aims to illuminate key principles of neuroblastoma evolution that drive and utilize metastasis to the bone marrow niche as a prerequisite to designing new therapeutic avenues in the long-term perspective that prevents and/or efficiently counteracts disease spread to and relapse in the bone marrow.
PhD positions and place of work: 1
1 wet-lab with interest in computational analyses (PI Simon Haas, BIH@Charité, Berlin)