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 currently consists of 2 postdocs and 3 technicians along with a master student. 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 studies drug development targeting tankyrase 1 and 2 (TNKS1/2), enzymes that regulate protein stability and cell signaling. TNKS1/2 regulate two key pathways: WNT/β-catenin and Hippo. In the WNT pathway, TNKS1/2 promote the degradation of AXIN1/2, leading to β-catenin stabilization and activation of WNT target genes. In the Hippo pathway, TNKS1/2 degrade AMOT proteins, which suppress YAP activity. As a result, YAP moves to the nucleus and activates genes related to cell proliferation. Both pathways are involved in processes like growth, differentiation and immune regulation, which are linked to diseases such as cancer and fibrosis.
Because of their central roles, TNKS1/2 are attractive drug targets. Oslo University Hospital, a leading center for chemical biology, has developed a small-molecule inhibitor program targeting these enzymes. The inhibitors stabilize key proteins like AXIN1 and AXIN2, suppressing WNT/β-catenin signaling, and modulate AMOT proteins in the Hippo pathway, leading to inhibition of YAP signaling.
About 40-65% of melanoma patients do not respond to immune checkpoint inhibitor (ICPi) therapy. ICPis are cancer therapies that block inhibitory pathways in T cells, helping the immune system better recognize and attack tumors. Resistance mechanisms are still being mapped, but pathways like WNT/β-catenin and YAP signaling have emerged as promising targets for therapeutic intervention.
β-catenin is the main transcriptional regulator of WNT/β-catenin signaling and plays a key role in immune evasion. In fact, β-catenin-driven immune resistance is seen in 42% of cutaneous melanoma cases. Currently, there are no available therapies that target WNT/β-catenin signaling to overcome ICPi resistance in melanoma.
At Oslo University Hospital, we have developed highly potent and specific preclinical-stage tankyrase inhibitors (TNKSi), OM-153 and OM-0815. These compounds are, to our knowledge, leading candidates for targeting WNT/β-catenin signaling in cancer. In a recent publication, we showed that TNKSi-mediated inhibition of this pathway can be used in combination with ICPis to overcome β-catenin-mediated resistance in melanoma.
However, the exact mechanisms how TNKSi modulates immune responses and affects ICPi sensitivity is not fully understood. We have found that TNKSi treatment leads to the accumulation of MITF in murine melanoma tumors. MITF is a key transcription factor involved in melanoma phenotype-switching and antigen presentation. Its stabilization may influence PD-L1 expression, cytokine release, immune cell infiltration, CD8+ T cell activity and overall response to ICPi therapy.
WNT/β-catenin and YAP signaling are both important regulators of MITF expression. Our preliminary results suggest that TNKSi treatment enhances tumor-immune cell interaction and promotes a productive immune response against tumors. (See figure below for the current model).
In this project, we will test TNKSi/ICPi in immune competent mouse models to investigate the underlying mechanisms.
Aims
Initial data indicate that the treatment enhances tumor-immune cell interactions, leading to changes in antigen presentation and activation of an adaptive immune response against tumors. This project will utilize immune-competent mouse models to investigate the mechanisms underlying the anti-tumor efficacy of TNKSi/ICPi treatment in melanoma.
- Evaluate anti-tumor efficacy and identify protein/RNA biomarkers related to WNT/β-catenin, YAP, and MITF signaling, as well as cytokine responses, in vivo.
- Investigate how TNKSi regulates WNT/β-catenin, YAP, and MITF signaling, and how these pathways contribute to the combined TNKSi/ICPi treatment effect.
- Define the role of MITF and YAP signaling alterations in mediating the therapeutic effects of the TNKSi/ICPi combination.
- Analyze TNKSi-induced tumor differentiation and phenotype switching.
- Examine immune cell activation and effector function in vitro.
- Characterize the tumor microenvironment and T cell responses in vivo.
Possible methods and techniques
- Cell culture and treatment with small-molecule inhibitors and siRNA
- Perform and analyze animal experiments
- Isolate lung cells and immune cell populations for single cell RNA sequencing
- T cell and macrophage killing assays
- Dendritic cell and T cell migration assays
- Flow cytometry and immune cell phenotyping
- Conduct ELISA and multiplex immunoassays.
- RNA extraction, RT-qPCR and RNA sequencing
- Western blotting, immunofluorescence and microscopy
We offer
- Research Involvement: Participate in a versatile and ambitious research project.
- Work Environment: Engage in an international, challenging, stimulating, and attractive research setting.
- 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.
Expectations for the Master’s student
- Commitment to the Project: Adhere to the project plan, adhere to ethical and institutional guidelines, and work with the supervisor to meet deadlines.
- Motivation & Initiative: Be highly motivated, proactive, and curious, with a strong interest in working in an internationally competitive laboratory.
- 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 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:
- Ole Vidhammer Bj?rnstad, PhD (Postdoc), o.v.bjornstad@medisin.uio.no
- Fahri Saatcioglu, Professor IBV, fahri.saatcioglu@ibv.uio.no