Research projects

Group Lugli Our group is currently working on the implementation of the biopsy-based IBD-DCA score to support the prognosis of disease development and the prediction of treatment success in patients with chronic inflammatory bowel disease (IBD). In parallel, in collaboration with the Institute of Pathology at St Vincent's University Hospital in Dublin, we are developing an AI algorithm to automate the scoring.

Schematic overview of how information extracted from colorectal biopsies may be used to guide treatment strategy in asymptomatic patients diagnosed with inflammatory bowel disease during colon cancer screening.

Group Krebs The mechanisms leading to severe inflammatory lung disease in some COVID-19 patients are unknown. In this project, we will analyze the cells in the lung lavage of these patients and compare these findings with results from collaborators working on a mouse model of COVID-19. We hope so to reveal targets for COVID-19 therapy.

Graphical abstract 

Group Freigang Natural killer T (NKT) cells are innate-like T cells with powerful immunoregulatory functions that recognize self and microbial glycolipids presented by CD1d molecules. While the efficacy of NKT cell agonists has been explored in the immunotherapy of infectious diseases and cancer, the mechanisms that control CD1d antigen presentation and NKT cell activation in vivo still remain incompletely understood. This project characterizes pathways linking CD1d antigen presentation to lipid metabolism, and aims to define critical effector functions of NKT cells in microbial infections. 

Group Freigang Atherosclerosis-related diseases remain the leading cause of mortality worldwide; and chronic inflammation represents a major driver of disease progression. First clinical trials demonstrated the beneficial effects of anti-inflammatory therapies in CVD patients, a better understanding of the molecular mechanisms of vascular inflammation is required to develop more effective treatment strategies. Besides the well-studied impact of macrophages, also distinct lymphocyte populations, including regulatory T cells, modulate the underlying inflammatory process. In this project we investigate how systemic dyslipidaemia and the resulting metabolic perturbation in distinct immune cells subsets affects physiological immune responses and contribute to vascular immunopathology in atherosclerosis.

En face preparations of the mouse aorta. The atherosclerotic lesions induced by feeding a high fat diet were revealed by staining with Oil Red O

Group Freigang Invasive fungal infections have high mortality rates with limited therapeutic options. We previously identified the macrophage-secreted IL-1 receptor antagonist (IL- 1Ra) as an innate immune checkpoint that facilitates fungal dissemination and candidiasis pathology. We demonstrated that therapeutic IL-1Ra neutralization protects against lethal Candida sepsis in pre-clinical models, whereas interferon-driven amplification of IL-1Ra during viral infections exacerbates fungal disease. Based on our research findings, we are currently developing an innovative, proprietary therapy approach for sepsis for clinical application as part of an Innosuisse-funded translational project. In addition, we further explore IL-1/IFN I crosstalk mechanisms, including IL-1Ra, as potential biomarkers and therapeutic targets in microbial infections.

Immunofluorescence staining of an infected mouse kidney. The tissue dissemination of the fungus Candida albicans was visualized by staining of the fungal cell wall.

Group Krebs Inflammation is a driver of cancer. We have shown that IL-33 signaling is important for the development of myeloproliferative neoplasms (MPN), a type of blood cancer, and for promoting colorectal cancer (CRC) (Mager, J Clin Invest, 2015; Mertz, OncoImmunology, 2015; Pastille, Mucosal Immunol, 2019; Yeoh & Vu, Cytokine, 2022). We currently investigate the contribution of IL-33 to MPN progression and the cellular and molecular mechanisms underlying IL-33-dependent CRC. For these studies, we use patient-derived samples and mouse models.

Increased levels of IL-33 protein in bone marrow of MPN patients. IL-33: brown; CD34 (endothelial cells): red

Group Krebs The intestinal barrier is often disrupted during intestinal diseases, causing gut leakiness. We have previously shown that the protein ESRP1, a regulator of mRNA splicing in epithelial cells, has a critical function to maintain the integrity of the intestinal barrier (Mager et al., eLife, 2017). In this project, we further investigate how loss or reduction of ESRP1 leads to intestinal homeostasis and pathogenesis, including inflammatory bowel disease and colorectal cancer.

Bacteria (white arrows) penetrate the leaky intestinal barrier of Esrp1 mutant mice. Scale bars: 100 μm (from Mager et al., eLife, 2017)

Group Krebs The vertebrate immune system comprises the innate immune system, providing the first line of defense, and the adaptive immune system, which is triggered at a later stage and is responsible for memory. 
In this project, we use different murine models to better understand the role of specific genes in the regulation of these immune cell subsets and how disbalance in this process may lead to immunopathology in different disease contexts, including pathogen infection (Cardoso Alves, EMBO Reports, 2020).

Changes in immune infiltrate composition and transcriptomic landscape in the lungs of diseased mice with a defect in immunoregulation. A. Immune cells were isolated from lung tissues of healthy and diseased mice and analyzed by flow cytometry to distinguish between immune cell subtypes, which are displayed in a tSNE representation. B. Alternatively, lung innate immune lymphocytes were analyzed using single-cell RNA sequencing.

Group Lugli Immune checkpoint inhibitors are increasingly used in the adjuvant therapy of locally advanced, neoadjuvantly treated adenocarcinomas of the esophagus. Reliable predictive biomarkers are essential to identify the patient population that shows a significant response to immune checkpoint inhibitors. We are studying the transcriptome, methylome and immunohistochemical expression profile of immunomodulatory molecules in human tumor samples.  The aim is to identify key molecules that may influence the response to therapy.  In addition, the impact of neoadjuvant therapy on these immunomodulatory molecules will be investigated.

Identification of differentially expressed genes in esophageal adenocarcinomas depending on PD-L1 status

Group Vassella  This project investigates the mechanisms driving temozolomide (TMZ) resistance in adult recurrent IDH-wildtype glioblastomas, with a focus on synergistic microRNA (miRNA) networks that contribute to tumor relapse. Using a single-center paired cohort of good TMZ responders (relapse interval >1 year), we identified 13 miRNAs with highly correlated expression in the relapsed tumors. These miRNA hubs are hypothesized to act synergistically, regulating key resistance pathways such as DNA damage repair, tumor plasticity, and cell survival. Additionally, our analysis highlights their role in modulating oncogenic pathways, including Wnt and TGF-β signaling, which drive stemness, EMT, and adaptive resistance. Importantly, this study represents the largest miRNA cohort profiled to date. We are currently investigating the extent and specific perturbations of miRNA regulatory hubs in cases with short relapse intervals and poor therapy responses, aiming to identify miRNAs with prognostic and predictive value. Our established patient-derived glioblastoma stem cell models will be utilized to investigate whether these dynamic miRNA networks influence short-term and long-term therapeutic responses. By targeting these networks, we aim to sensitize glioblastoma stem cells to TMZ in vitro and in vivo, paving the way for miRNA-based therapies to overcome resistance. This work is supported by Krebsliga Bern and Stiftung Für Klinisch-Experimentelle Tumorforschung SKET (to E. Kashani).

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. 

Group Schenk The tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC) is diverse, comprising various cell types that may either enhance or attenuate tumor immunity and disease progression, as well as response to therapies. It is therefore essential to dissect the immunological landscape in human PDAC tissues and to assess the correlation of various cell subsets and tumor-derived immunosuppressive factors to patient survival and other clinical parameters. Utilizing a novel approach to perform spatially resolved multiplex immunohistochemistry, we intend to delineate the phenotypes of tumor-infiltrating immune subpopulations in exquisite detail. Integrating these findings with transcriptomic data and tumor genotype signatures will allow us to unravel the mechanistic and prognostic relevance of certain immune markers in PDAC.

25-plex imaging mass cytometry (IMC) image of a human PDAC tissue section shown in four images with 6 markers each. Overview (top), zoom (bottom)

Group Lugli The main aim of the GI Tissue Medicine research group concerning tumor budding in CRC is the following: to identify potential target molecules in tumor buds and develop an anti-budding therapy. The focus lies on four clinical scenarios: pT1 CRC, stage II CRC, rectal cancer (preoperative) and colorectal liver metastases. Additionally, our group is also a member of the International Budding Consortium (IBC).  

pT1 colorectal cancer with high grade budding (H&E staining)

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

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 were able to show that the response measured in vitro highly correlated with the response of the patient to the same drug in the clinic, suggesting that our model could be used for precision medicine in PanNEN. 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 organoids from the organoid line PKNEC5, stained with sytoxgreen = green= cell death, MitoTracker orange = yellow = mitochondrial activity, CellRoxDR = Red = cellular ROS, and Hoechst 33342 = blue = DNA stain. Captured at 40x with the Yokogawa CQ1 confocal micorscope

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. 

Group Tschan Elevated HK3 expression levels are characteristic of monocytic AML. Notably, high HK3 expression correlates with reduced initial responsiveness and the development of secondary resistance to the BCL2 antagonist venetoclax. We propose that HK3 promotes AML cell survival and attenuates therapeutic responses through non-metabolic mechanisms.

HK3 expression in AML cells is associated with intrinsic resistance to venetoclax (ABT-199)

Group Tschan Desmoplasia is characterized by the excessive deposition of extracellular matrix (ECM) components, such as collagen, and is associated with increased tumor aggressiveness. Cancer-associated fibroblasts (CAFs) are major contributors to desmoplastic remodeling. Our ITMP collaborative research team will investigate the potential role of CAF autophagy in this process.

Modulating autophagy in breast cancer CAFs

Group Tschan We found that knocking down the oncogenic DMTF1β isoform reduces migration and invasion of prostate and breast cancer cells. Interestingly, this was accompanied by the downregulation of autophagy-related pathways and autophagic flux. Mechanistically, we identified the autophagy protein ULK1 as a novel interaction partner of DMTF1β, whereby DMTF1β promoted ULK1 protein stability. Additionally, we discovered that DMTF1β is a short-lived protein that undergoes polyubiquitination in a β-domain-specific manner, leading to proteasomal degradation.

β-specific domain DTMF1β is associated with poly-ubiquitination

Group Schenk Our research group employs cutting-edge methods to uncover key cellular mechanisms and molecular markers in atopic dermatitis (AD), aiming to identify innovative therapeutic targets and biomarkers. We study both adult and pediatric AD cohorts, focusing on interactions between innate and adaptive immunity, trained immunity, and immunoregulatory pathways. Our proteomic analyses have identified molecules modulating inflammation, revealing potential therapeutic strategies. Using advanced technologies like CITE-seq, CyTOF, imaging mass cytometry (IMC), and spatial transcriptomics, we investigate immune cell subsets and marker expression in blood and skin lesions, providing comprehensive insights into systemic and localized immune dynamics. Potential therapeutic targets are validated in murine AD models. Additionally, we explore the skin microbiome's composition and its critical role in AD, understanding its significant impact on immune responses and disease outcomes.

28-plex IMC image showing structural features, immune phenotypes, and activation markers in healthy skin (top) atopic dermatitis (bottom)

Group Schenk The activation of an effective adaptive anti-tumor response relies mainly on presentation of tumor antigens and stimulation by DC. Despite extensive research, the phenotypes and functions of tumor-infiltrating DC (TIDC) remain largely elusive and cross-presentation of tumor antigen is not well understood. We are elucidating the phenotypes and functions of TIDC and how to manipulate them both in vitro and in vivo to induce a tumor- specific CTL response in melanoma. Thereby, we aim to identify ways to reprogram TIDC to present tumor antigens and activate an adaptive immune response against melanoma.

Group Vassella  We conducted CRISPR/CAS interference library screens and identified SMG1, implicated in an evolutionarily conserved RNA quality control pathway - the nonsense-mediated mRNA decay (NMD) pathway. NMD leads to the degradation of transcripts containing premature stop codons, often occurring after temozolomide treatment. NMD may influence the mechanisms employed by tumour cells to repair DNA damage caused by temozolomide treatment. Hence, we hypothesise that the enhanced temozolomide response is due to reduced DNA repair capacity in SMG1-attenuated glioblastoma cells. The aim of this work is to further investigate the mechanisms leading to an enhanced temozolomide response in glioblastoma cells with attenuated SMG1. Since NMD efficiently suppresses truncated proteins, which are highly immunogenic, we hypothesise that SMG1 inhibition in temozolomide-resistant, recurrent glioblastoma may elicit tumour inflammation. Hence, we expect that NMD improves the treatment response to immune checkpoint inhibitors. This work is currently supported by the Swiss Cancer League.

Heat map analysis of recurrent glioblastoma

Group Vassella Glioblastoma is the most common and most aggressive primary malignant brain tumour in adults. We performed expression profiling of patient-matched primary and recurrent glioblastoma samples and identified differential gene expression patterns indicative of enhanced activin signalling in recurrent tumours. To investigate the functional role of activin signalling in glioblastoma, we modulated this pathway in primary glioblastoma cells both in vitro and in vivo, focusing on its contribution to resistance against alkylating agent therapy and its impact on shaping the tumour microenvironment. This study may have significant clinical relevance, as pharmacological inhibition of activin signalling could be exploited in combination therapies to improve responses to chemoradiation or immune checkpoint inhibitor treatment in recurrent glioblastoma.

Temozolomide (TMZ) response in spheroid cultures of glioblastoma cells with wild-type (WT), activin- high (CA), or activin-low (DM) signalling states

Group Vassella Medulloblastomas are the most common aggressive pediatric brain tumors, molecularly defined by different groups and subgroups. Although medulloblastoma is a rare disease, it has been also described in postpubertal and adult patients. The lack of studies exclusively on adult medulloblastomas means that the therapeutic approach in these patients is mainly based on existing data from studies on pediatric medulloblastomas. For these reasons and given that adult patients do not have a satisfactory clinical outcome after therapy, we would like to study a large cohort of adult medulloblastomas and medulloblastoma relapses on a clinical, pathological and molecular level in order to further characterize the biology of these tumors for developing a targeted therapy adapted to their molecular profile.

Classic histomorphology of an adult medulloblastoma

Group Zlobec, Williams The extracellular matrix (ECM) forms part of the triad of the tumour ecosystem but is understudied in terms of its contribution to tumour biology. The Williams group utilises spatially resolved multi-matrisomics (spatial transcriptomics, proteomics and digital image analysis) in 2D and 3D to deeply characterise the structural and biochemical manifestations of the matrisome and the association of this to tumour biology and its clinical relevance for patient outcome. We work across a variety of solid tumour types including colorectal cancer and pancreatic ductal adenocarcinoma. Our current interests include: structural and biochemical phenotyping of the ECM across 2D and 3D modalities, the ECM and epithelial identity and CAF mechanisms of desmoplasia. 

Multi-modal assessment of extracellular matrix in solid tumours

Group Zlobec, Williams In addition to exploratory tissue analysis, our team develops, tests, and validates in-house, open-source, and commercially available algorithms for potential diagnostic use and seamless workflow integration. We are currently generating a pan-lymph node metastasis algorithm (MetAssist) using state-of-the-art deep learning methods. We optimise the entire process, from laboratory workflows to data analysis, and support the visualisation of results and interaction between our algorithms and pathologists’ assessments. By integrating pathologists feedback, our goal is to enhance the performance of MetAssist and deliver a reliable nodal screening tool to assist pathologists in routine clinical practice on several tissue types. We work closely with our expert pathology colleagues for this purpose.

Computational Analysis of Metastases in Multi-cancer Lymph Nodes

Group Zlobec, Williams The goal of this SNF-funded project is to elucidate metastatic pathways, from lymph node metastases (LNM) to tumour deposits (TD), using 2D and 3D analyses. As the clinical partner in this multi-institutional collaboration, our group is responsible for the morphological and spatial mapping of LNM and TD in 2D to assess their metastatic potential and generate insights that may refine current clinical and biological paradigms. Our 2D observations will inform subsequent 3D analysis using microCT, nanoCT, and 3D light-sheet fluorescence microscopy (LSFM), enabling 2D observations to be visualised in a volumetric context. Through this integrated framework, the project aims to provide a more comprehensive understanding of CRC metastatic evolution.

Computational analysis reveals that the presence of tumor budding and complex tumor morphology in LNMs is linked to worse prognosis

Group Zlobec, Williams Our group leverages single-cell spatial transcriptomics (GeoMx, CosMx) to decode the biology of solid tumors in unprecedented detail. We focus heavily on technical rigor, benchmarking data acquisition and analysis pipelines to ensure robust biological interpretation. By integrating tissue morphology with underlying molecular states, we have identified novel independent prognostic biomarkers, such as a tumor-interaction score linking cancer-stromal engagement to inflammation and extracellular remodeling. Furthermore, we investigate predictive markers for radiotherapy response, connecting tumor shrinkage to glutamine-related gene transcription. Ultimately, our work combines deep biological analysis with clinically relevant insights to improve patient stratification.

Morpho-molecular analysis. (a) PanCK-stained TMA core. (b) Single-cell segmentation showing the tumor-interaction score (epithelial) vs. TME (grey). (c) Visualization of tissue acquisition and downstream single-cell phenotyping within a selected field of view