Epigenetic changes and tumor cell heterogeneity in the progression of PanNETs 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. Graphical representation of PanNET progression
Precision medicine approach for PanNET treatment 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 PanNEN patients which resemble features of original tumor tissue and which can be used for in vitro drug screenings. We demonstrated the utility of PanNEN tumoroids to predict patient therapy response and we identified novel epigenetic treatment options. Recently we established xenograft of PanNEN on Zebrafish embryos to further exploit in precision medicine. Precision medicine for PanNEN patient. PanNEN tumoroids in culture, H&E staining and synaptophysin staining of embedded tumoroids (middle). Zebrafish xenotransplant, red: tumor cells, green: endothelial cells.
Metabolic changes in PanNET 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 and develop distinct metabolic subtypes. 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 by modern mass spectrometry, fluorescence microscopy and RNAseq data will delineate these metabolic changes and test novel therapeutic strategies. (A) Tissue mass spectrometry identified five metabolic subtypes. (B) Immunohistochemistry and (C) Fluorescence microscopy show metabolic heterogeneity.
An early offensive against acquired therapy resistance in PanNET Group Perren Acquired drug resistance (ADR) is a major clinical challenge to all current and future cancer treatments, including chemo, radiation, targeted, and immune therapies and accounts for 90% of cancer mortality. Due to the stochastic, nature of mutation-driven ADR, multiple different resistance mechanisms can 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. (A) DTPs precede acquired drug resistance (ADR). (B) Time laps fluorescence microscopy of PanNET shows therapy-induced loss of sensitive cells and emergence of DTPs. Single-cell phenotypic and molecular analysis to identify drugs for repurposing against (DTPs.
