Waaler lab, Department of Immunology, Oslo University Hospital
The Cell Signaling and Drug Discovery research group is located at the Department of Immunology (IMM) at Oslo University Hospital – Rikshospitalet and is led by Group Leader Jo Waaler www.ous-research.no/waaler. The group will consist of 2-3 postdocs and 2-3 technicians along with Master's students. The research group is also associated with the RCN Centre of Excellence (SFF) - Hybrid Technology Hub - Centre for Organ on a Chip-Technology: www.med.uio.no/hth/english. Jo Waaler has functioned as a supervisor for 11 Master’s students.
Background
The research group focuses on tankyrase 1 and tankyrase 2 (TNKS1/2), enzymes from the PARP family that regulate protein activity, interactions, and degradation through mono- or poly-ADP-ribosylation and downstream cell signaling. TNKS1/2 proteins are key players in the regulation of WNT/β-catenin and Hippo signaling pathways, which are implicated in various diseases, including cancer, immune evasion and fibrosis. Consequently, significant efforts have been dedicated to developing selective TNKS1/2 inhibitors.
Oslo University Hospital has established itself as a leading center for chemical biology and has developed a small-molecule TNKS inhibitor program. These inhibitors modulate several target proteins, such as AXIN1 and AXIN2 in the β-catenin destruction complex, thereby inhibiting WNT/β-catenin signaling, and AMOT proteins in the Hippo signaling pathway, leading to YAP signaling inhibition.
40-65% of melanoma patients do not respond to immune checkpoint inhibitor (ICPi) therapy. Resistance mechanisms are currently being mapped, and cellular signaling pathways, such as YAP and WNT/β-catenin signaling, emerge as promising targets for therapeutical intervention. β-catenin is the key transcriptional regulator of WNT/β-catenin signaling, and β-catenin-induced immune evasion is found in 42% of cutaneous melanoma. Currently, there are no therapeutical strategies available for targeting WNT/β-catenin signaling to counteract ICPi resistance in melanoma. At Oslo University Hospital we have discovered a higly potent and specific preclinical stage tankyrase inhibitors (TNKSi, OM-153 and OM-0815). To our knowledge, OM-153/OM-0815 are leading the field for its bio-target and for a therapeutic WNT/β-catenin signaling inhibitor. In a recent publication, using TNKSi-mediated blockade of WNT/β-catenin signaling, we uncover a novel combinatorial therapeutical strategy to overcome β-catenin-mediated resistance to ICPi therapy in melanoma. However, the precise mechanism behind TNKSi-mediated regulation of immune regulation and control of susceptibility to ICPi therapy is not properly characterized. We have recently discovered that TNKSi can induce accumulation of MITF in murine melanoma tumors. MITF is a central transcription factor involved in melanoma phenotype-switching and antigen presentation. MITF stabilization can lead to altered antigen presentation, PD-L1 expression, cytokine release, immune cell infiltration, enhanced CD8+ T cell cytotoxicity and increased sensitivity to immune checkpoint inhibition. WNT/β-catenin and YAP signaling are central regulators of MITF expression. Our initial efficacy data point towards a beneficial stimulation of the tumor-immune cell interplay resulting in an adaptive immune response targeting tumors (see current model in figure). In this project we will test TNKSi/ICPi in immune competent mouse models for detailed mechanistic studies.
Aims
The initial efficacy data strongly suggests a beneficial stimulation of the tumor-immune cell interplay, resulting in significant alterations in antigen presentation and the activation of an adaptive immune response targeting tumors. Our project will utilize immune-competent mouse models to conduct in-depth mechanism-of-action studies on the synergistic interaction between TNKSi-ICPi in melanoma treatment. The primary objective is to identify the mechanisms responsible for the anti-tumor efficacy of the TNKSi/ICPi treatment.
- Analyze anti-tumor efficacy and protein/RNA biomarkers for WNT/β-catenin, YAP, and MITF signaling as well as cytokines in vivo.
- Assess the contribution of altered MITF and YAP signaling to the combinatorial treatment effect.
- Deconvolute the mechanism behind TNKSi-mediated regulation of WNT/β-catenin, YAP, and MITF signaling
- Evaluate TNKSi-induced differentiation and phenotype switching.
- Test immune cell activation and effector function in vitro.
- Assess tumor microenvironment and T cell activation/effector function in vivo.
Possible methods and techniques
- Conduct cell culture experiments.
- Perform dendritic cell and T cell migration assays.
- T cell and macrophage “killing assays”.
- Perform and analyze animal experiments.
- Isolation of lung cells and immune cell populations.
- Perform flow cytometry, immune cell phenotyping and scRNA sequencing.
- Conduct immunoassays/ELISA and multiplex ELISA.
- Basic laboratory and cell signaling pathway analysis techniques: i.e. treatment with small-molecule inhibitors and siRNA, CRISPR-Cas9 gene knockout, real-time RT-qPCR, RNA sequencing, Western blot analysis and immunofluorescence/immunohistochemistry/microscopy.
We offer
- Work Environment: Engage in an international, challenging, stimulating, and attractive research setting.
- Research Involvement: Participate in a versatile and ambitious research project.
- Career Development: Receive opportunities and support to advance your career.
- Technical Training: Gain hands-on experience with both basic and cutting-edge techniques in cancer/cell biology, molecular biology, and mouse animal models.
- Publication & Strategy: Collaborate with your supervisor to develop research strategies and receive proper credit for work aimed at publication in international peer-reviewed journals.
- Scientific Communication: Develop dissemination skills through training in oral presentations and scientific writing.
- Collaborative Learning: Participate in weekly lab meetings and journal clubs to share expertise and receive support in literature searches.
- Community & Social Events: Take part in regular social activities, including summer and Christmas parties, as well as group retreats.
What we expect from the Master’s student
- Motivation & Initiative: Be highly motivated, proactive, and curious, with a strong interest in working in an internationally competitive laboratory.
- Commitment to the Project: Stay faithful to the project plan, adhere to ethical and institutional guidelines, and work with the supervisor to meet deadlines
- Time Management: Be a full-time student who takes responsibility for planning and managing your own time effectively.
- Literature & Understanding: Read relevant literature and dedicate significant time to fully understand the project.
- Independence & Collaboration: Aim to become an independent laboratory worker after the training period (1–2 months) while recognizing when to seek help.
- Presentation Skills: Present your work in internal/external meetings to develop communication skills and prepare for your final examination.
Contact Persons
Main supervisor:
- Jo Waaler, PhD (Group leader), jo.waaler@medisin.uio.no
Co-supervisors:
- Postdoc in the group