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.
Metastatic-on-Chip Model
Gruppe Guenat The Metastasis-on-Chip project aims to replicate the metastatic process, focusing specifically on extravasation and colony formation. Our initial studies evaluate the metastatic potential of cancer cells based on their phenotypes, using the A549 non-small cell lung cancer (NSCLC) cell line, which exhibits distinct phenotypic variations. We discovered that paraclones, characterized by a mesenchymal phenotype, successfully extravasate, while holoclones, with an epithelial phenotype, do not. Additionally, paraclones demonstrated significantly greater migratory behavior compared to holoclones. These findings provide valuable insights into the mechanisms of metastasis and lay the groundwork for further exploration of targeted therapies.
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.
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.