Group Marinoni, Perren, Sadowski

Group Perren We focus on understanding epigenetic changes occurring in PanNET and their impact on progression and metastasis formation. Based on DNA methylation we identified subgroups of PanNETs with: specific cell of origin, genetic background and clinical outcome. Integrating epigenetic and transcriptomic profiles we found that cell dedifferentiation and metabolic changes characterize progression from small PanNET to more advanced ones. We are currently investigating spatial and temporal heterogeneity of PanNET using multi-omic approaches.

Top: Phyloepigenetic analysis of PanNET human samples and normal alpha and beta-cell samples.  Bottom: Progression model hypothesis based on epigenetic and genetic evolution

Group Perren Up to date, no therapy prediction based on specific molecular profile is possible for PanNET patients. We recently established patient-derived tumoroid cultures from PanNET patients which resemble features of original tumor tissue and which can be used for in vitro drug screenings. We are currently assessing the utility of PanNET tumoroids to predict patient therapy response and to identify novel epigenetic treatment options. Also, we aim at identifying specific molecular profiles through DNA sequencing, methylation- and gene expression analysis to predict therapy response in vitro and on the patients.

Patient-derived Tumoroids from PanNET patients are utilized for in vitro pharmacotyping and molecular profiling

Group Perren Critical metabolic changes are early hallmarks of cancer cells. Emerging epigenetic, transcriptional and translational data suggest that PanNET cells undergo substantial metabolic reprogramming. However, the identity, functional consequences and therapeutic potential of metabolic changes in PanNET remain up until now largely unknown and untested. Our multimodal, integrated analysis of PanNET cell culture and tissue samples of various stages of tumor development by modern mass spectrometry, fluorescence microscopy and RNAseq data will delineate these metabolic and test novel therapeutic strategies.      

Tissue mass spectrometry (top) identified five metabolic PanNET. Fluorescence microscopy measured mitochondrial activity (middle) and lipid storage (bottom) in PanNET cells

Group Perren Acquired drug resistance (ADR) is a major clinical challenge to all current cancer treatments, including chemo, radiation, targeted, and immune therapies and accounts for 90% of cancer mortality. Given the stochastic, mutation-driven nature of ADR, multiple different resistance mechanisms often co-evolve within in the same tumour or across metastatic lesions in the same patient, requiring individualized therapeutic approaches. This project seeks to identify and test novel strategies to target drug- tolerant persister cells (DTPs), which comprise an early, reversible bottleneck phase of ADR. RNAseq and high content imaging-guided molecular and phenotypic analysis will delineate the early dynamic changes during DTP development in 2D and 3D ADR models of PanNET.

Graphical description of the three phases of acquired drug resistance and associated phenotypes (right) with corresponding micrographs (left) of chronically treated PanNET spheroids showing hallmarks of DTPs (enhanced lipid peroxidation).