Cell Biology

Understanding role of Ribonuclease inhibitor (RNH1) in Myelopoiesis and Myeloid Malignancies

Group Allam   Our previous investigations have unveiled a crucial function of Ribonuclease inhibitor (RNH1) in regulating homeostatic hematopoiesis. In the absence of RNH1, the balance in hematopoiesis was skewed significantly to favour myelopoiesis at the expense of lymphoid and erythroid lineage cells. It has also been observed from our in-vivo mice studies that the increase in myelopoiesis however, did not culminate in a leukemic transformation. The ongoing project is aimed at elucidating the mechanism behind the RNH1 mediated exacerbation of myelopoiesis under homeostatic conditions and the implications of genetically modifying RNH1 expression in myeloid malignancies. For this, we are utilizing AML in-vitro (cell lines) and in-vivo (mouse) models along with AML patient derived cells. Our research so far has highlighted an involvement of RNH1 in the AML pathophysiology and ongoing studies are attempted at discerning a therapeutic potential of targeting RNH1 in myeloid malignancies.

Next-generation CAR T cells for pediatric rhabomyosarcoma

Group Bernasconi & Rössler   We aim to improve existing therapies for pediatric solid tumors and to devise more effective and less toxic therapies, with a particular focus on rhabdomyosarcoma. 
Pediatric sarcomas account for about 15% of pediatric cancers. The relapse rate is generally high with extremely poor prognosis. CAR T cells are engineered T cells expressing chimeric antigen receptors (CARs). CAR T cells therapy is one of the most promising approaches against relapsed or otherwise untreatable cancers.
Since 2018, our laboratory focuses on this personalized immunotherapy, in order to enhance the normal capacity of the patient's immune system to recognize and attack the tumor. We have investigated rhabdomyosarcoma surfaceome by proteomics and we have identified several targets for CAR T cells. We are now conducting in vitro and in vivo experiments to improve CAR T cells activity against rhabdomyosarcoma.

Dissecting the role of tumor cell heterogeneity in Pancreatic Neuroendocrine Tumor progression

Group Marinoni, Perren, Sadowski   Cancer is a dynamic disease; genetic and epigenetic alterations drive intra-tumoral cell heterogeneity, resulting in the selection of aggressive cell populations capable of driving progression and ultimately metastasis. Pancreatic neuroendocrine tumours (PanNETs) are tumours that arise from the islets of Langerhans. They exhibit intra-tumoral cell heterogeneity, but it is unclear how this evolves during tumour development and how it contributes to progression. Our previous data suggest that epigenetic changes are the major drivers of progression and cell heterogeneity in PanNETs. By integrating epigenetic and transcriptomic profiles, we found that cell dedifferentiation and metabolic changes characterise the progression from small PanNETs to more advanced ones. We are currently investigating the evolution of intra-tumoral heterogeneity of PanNETs through space and time. Specific cell subpopulations identified as driving progression could then be targeted to stop metastasis formation. The identification of targetable pathways that impair metastasis formation will provide a rationale for new treatments.nd Zeit hinweg. Spezifische Zellsubpopulationen, die als treibende Kraft des Fortschreitens identifiziert wurden, könnten dann gezielt therapeutisch angegangen werden, um die Metastasenbildung zu stoppen.

Targeting cellular metabolism to augment cancer therapy

Group Marti   The aim of this project is to investigate how the nucleotide/lactate metabolism and the DNA damage response machinery are associated with the tumor initiating capacity, the chemotherapy response, and the metastatic capacity of lung and mesothelioma cancer stem cells. In addition, we are exploiting treatment induced cellular adaptations as novel targets for cancer therapy.

Oncogenic signaling via receptor tyrosine kinases in crosstalk with DNA damage repair

Group Medova   Tyrosine kinase receptors activate a wide range of different cellular signaling pathways. Physiologically, intact signaling via the MET receptor is indispensable in embryonic development and tissue homeostasis. At the same time, MET dysregulation promotes features clearly associated with tumor growth and progression such as uncontrolled proliferation, angiogenesis, local invasion, and systemic dissemination. Accumulating data suggest that MET signaling may also protect tumor cells from DNA damage, hence relating its aberrant activity to resistance to DNA-damaging agents routinely used in cancer treatment. We have identified a previously unreported phosphorylation site on MET, which can be recognized by DNA damage master kinases and is involved not only in cellular responses towards DNA damage, but also in metastatic processes, cancer cell migration, and anchorage-independent growth. This project aims at dissecting the nature, function, and regulation of this phosphorylation site in oncogenic signaling of the receptor.

Myeloid Malignancies

Group Meyer   Myeloproliferative neoplasms (MPN) are chronic leukemias characterized by constitutive activation of JAK2 tyrosine kinase signaling. Clinical JAK2 inhibitors bring benefits for patients, but have limited disease-modifying activity. Allogeneic hematopoietic cell transplantation is the only curative treatment to date.
The Meyer lab has a specific interest in the oncogenic signaling driving MPN. We have demonstrated that activation of the MAPK pathway with MEK1/2 and ERK1/2 kinases, which is involved in several cancers, limits JAK2 inhibitor therapy and needs to be adressed to enhance efficacy (Stivala, JCI 2019; Brkic, Leukemia 2021). These findings have translated to a clinical study (Adore, NCT04097821).
Our lab is investigating mechanisms of resistance, which mediate loss of response to clinical JAK2 inhibitors, and approaches to overcome resistance. Notably, we are involved in the characterization of novel types of JAK2 inhibitors incl. type II JAK2 inhibitors currently in development towards clinical studies (Meyer, Cancer Cell 2015; Codilupi, CCR 2024).



The interaction between immune cells and leukemia/cancer stem cells

Group Ochsenbein   Our research unit examines the interaction between immune cells and cancer stem cells with a focus on leukemia stem cells. Cancer stem cells are resistant to most of the currently available drugs and are responsible for relapse after successful chemotherapy. We use state of the art techniques to analyse the molecular interactions between immune cells and cancer stem cells in murine models and in clinical samples from cancer patients. The aim is to develop improved immunotherapies that specifically target cancer stem cells for different types of cancer, especially in hemato-oncological diseases such as leukemia and multiple myeloma. These novel durgs are tested in in preclinical models and in clinical phase 1 and 2 studies.

Design, synthesis, analysis, and optimization of novel small molecule inhibitors against prostate cancer

Group Pandey   Androgens are linked to pathology of prostate cancer. Cytochrome P450 CYP17A1 and Aldo-keto reductase AKR1C3 involved in steroid metabolism are drug targets. The current anti-prostate cancer drug, abiraterone, targeting CYP17A1, is not very effective, and has side effects. We found that Abiraterone inhibits CYP21A2 and cortisol production; and a metabolite of abiraterone is a potent androgen, which ultimately defeats the treatment. With computational and medicinal chemistry groups from Denmark, Poland, Italy and Spain, we produce novel inhibitors of CYP17A1 and AKR1C3.
We design and improve the compounds and test them in the laboratory. After the virtual screening, we apply machine learning and automated workflows to identify pharmacophores for structural modifications and synthesis of novel chemicals. Nanoparticle based delivery is used to enhance the efficacy. Using several cell and recombinant protein models novel inhibitors are being tested which are now working at nano molar levels.

Leukemia stem cells and the bone marrow microenvironment

Group Riether   The bone marrow (BM) microenvironment is a unique cellular architecture which crucially regulates self-renewal and differentiation potential of hematopoietic stem and progenitor cells through cell-cell interaction or the release of soluble mediators. These evolutionary conserved processes that evolved to protect normal hematopoietic stem cells from elimination and to regulate demand-adapted responses during inflammation are frequently hijacked in cancer and leukemia. The goal of our research is to understand the molecular and cellular mechanisms how different components of the BM microenvironment such as immune cells and stromal cells affect disease-initiating and -maintaining leukemia stem cells (LSCs) and protect them from immune-mediated elimination. We take advantage of state-of-the art technologies, well-established chronic and acute myeloid leukemia mouse and patient-derived xenograft models in order strengthen our understanding on LSCs and to translate our findings into human disease.

Cancer cell motility supported by oncogene induced autophagy

Group Tschan   We discovered an oncogenic splice variant of the tumor suppressor and transcription factor DMTF1 active in the p53 pathway. We found that this splice variant, DMTF1β, promotes breast cancer cell motility by activating autophagy. We are currently unravelling mechanisms how DMTF1β is regulated and how it promotes cancer cell motility by activating autophagy. Our aim is to identify tumor types and cellular conditions where common cancer therapies in combination with autophagy inhibition is beneficial to block migration.