Ongoing Projects

Contribution of TP53 and RB1 to lineage plasticity prostate cancer (Dr. Seynabou Diop, Postdoc)

We are investigating the contribution of RB1 and TP53 loss of function to the development and progression of AR-negative metastatic castration-resistant prostate cancer (ARN mCRPC including double-negative prostate cancer (DNPC) and neuroendocrine prostate cancer (NEPC)). We plan to identify genes which in combination with loss of function of TP53 or RB1 have clinical relevance such as resistance to AR-directed therapy and evidence of cell plasticity including neuroendocrine characteristics. 

Dynamics in lineage plasticity (Dr. Irene Paassen, Postdoc)

Treatment resistance in prostate cancer (PCa) is an emerging problem worldwide due to increasing numbers of diagnoses. Development of targeted therapies for PCa, lead to the outgrowth of resistant tumors with altered lineage identity compared to pre-treatment tumors. The cellular and molecular mechanisms that underlie treatment-associated lineage transitioning remain poorly understood. Growing evidence suggests that epigenetic regulation may play an essential role. One major determinant of cell identity in both, disease and development, is the SWI/SNF chromatin remodeler complex. In this project we aim to elucidate its role controlling lineage transition in PCa. 

We will utilize RPM (= Rb1-/-; Trp53-/-; MycT58A) PCa organoids, which recapitulate lineage transitioning in vivo toward a treatment-resistant PCa subtype. A barcoded CRISPR screen targeting subunits and targets of the SWI/SNF complex for gene-knockout will be performed in this model system. Following subcutaneous injection of barcoded organoids into mice, tumors will be extracted at multiple time points and analyzed using combined single-cell RNA and ATAC-sequencing. The use of state-of-the-art technologies on this unique model system will provide novel insights into the SWI/SNF-controlled chromatin landscape and clonal dynamics underlying lineage transition in PCa. 

This project is supported by the US Department of Defense and the Wilhelm Sander Stiftung.

Macrophage targets for metastatic treatment Mac4Me (Marine Cuiller, PhD Student)

Although survival of patients presenting advanced cancer with brain metastasis (BrM) has improved with recent therapeutic advances, treatment responses are highly variable and associated with severely affected quality of life. Despite the great promise of immunotherapies, their effectiveness and relevance in BrM remain unclear due to limited trial inclusion and the unique immune profile of metastases. 

To address this clinical challenge, our project, part of the Mac4me MSCA-Doctoral Network, focuses on understanding the early, dynamic interplay between tumor cells and two key components of the brain microenvironment that shape the immunosuppressive niche of BrM: brain-resident macrophages (microglia), specifically investigating their pro-tumorigenic phenotype reprogramming, and extracellular matrix (ECM) remodeling, analyzing its impact on both immune cell activity and tumor cell invasiveness. We selected breast and prostate cancers as models, as breast cancer frequently spreads to the brain, whereas prostate cancer BrM, although rare, show a growing incidence rate. We will develop an advanced in vitro brain-metastasis model by encapsulating human stem cell–derived brain organoids in a brain-mimetic hydrogel integrated into the MIVO® organ-on-chip device. Prostate and breast cancer cells will be introduced into the system under flow, enabling real-time monitoring of tumor cell migration and interactions with the brain microenvironment. Using live cell imaging, immunofluorescence, functional assays, molecular profiling, and mechanical characterization, we will investigate microglial responses and ECM alterations during metastasis initiation. These insights will support the development of a screening platform for therapeutics, including microglia-targeted treatments, aimed at disrupting the formation of the immunosuppressive metastatic niche. 

This project received funding from the SERI for the EU MSCA Doctoral Network. 

To learn more about the Mac4me consortium, check : https://mac4me.eu

Understanding non-canonical phosphatidylinositol kinases as vulnerabilities in prostate cancer metabolism (Dr. Joanna Triscott, Senior Postdoctoral Scientist)

Phosphatidylinositol regulating enzymes have a high frequency of alteration in advanced prostate cancer. In this project we are the first to investigate PI5P4K in prostate biology. This lipid kinases family is implicated in cell stress and cancer metabolism, as well, may have a signaling interplay with key drivers of cancer progression. We have developed novel animal models, queried metabolism pathways in vitro, and implemented multi-omic tools to characterize the impact of PI5P4K depletion in prostate cells. Our long-term goal is to untangle the role for PI5P4K in the context of prostate cancer in order to establish the rationale for developing PI5P4K inhibitors for clinical application.

This project has been funded by the Swiss National Research Foundation, the Marie Skłodowska-Curie Actions (MSCA), and the Johanna Dürmüller Bol foundation.

Towards understanding the role of the minor spliceosome in prostate cancer (Dr. Anke Augspach, Postdoc)

Alternative splicing, a process by which a single message (referred to as RNA) can give rise to several different proteins represents a non-genetic variability known to play a major role in cancer development and progression, yet the precise molecular mechanisms by which the various splice variants are generated remain unclear. Splicing is carried out by two large and complex molecular machines. While the major mechanism, responsible for more than 99% of all splicing, is well characterized, the minor mechanism is poorly understood. In this project, we aim to further understand the role of the minor spliceosome in (prostate) cancer development and resistance to pave the way for new therapeutic and diagnostic tools for high-risk/advanced (prostate) cancer patients.

We currently have our first study in late revision stage at Cell. In this first study, we explored the role of minor spliceosome (MiS) and minor intron-containing gene (MIG) expression in prostate cancer (PCa). We show MIGs are enriched as direct interactors of cancer-causing genes and their expression discriminates PCa progression. Increased expression of U6atac MiS snRNA, including others, and 6x more efficient minor intron splicing was observed in castration-resistant PCa (CRPC) versus primary PCa. Notably, androgen receptor signaling influenced MiS activity. Inhibition of MiS through siU6atac in PCa caused minor intron mis-splicing and aberrant expression of MIG transcripts and encoded proteins, which enriched for MAPK activity, DNA repair and cell cycle. Single cell-RNAseq confirmed cell cycle defects and lineage dependency on the MiS from primary to CRPC and neuroendocrine PCa. siU6atac was ~50% more efficient in lowering tumor burden of CRPC cells and organoids versus current state-of-the-art combination therapy. In all, MiS is a strong therapeutic target for lethal PCa and potentially other cancers. Based on these observations, the University of Bern has filed a patent application in the area of diagnostics and therapeutics and we are in the process of starting a company around a minor spliceome platform for cancer and viral therapy.

This project has been funded by a Fond’action contre le cancer young investigator award and Prostate Cancer Foundation Challenge Award.

Towards understanding and modulating epigenetic rewiring in AR-indifferent PCa (Phillip Thienger, PhD student)

This project seeks to understand the lineage plasticity of AR-indifferent PCa, which will help create therapeutic approaches that can delay or inhibit terminal forms of PCa and lead to earlier co-targeted therapies prior to disease progression. In preliminary work, we have identified chromatin remodeling complexes, such as the SWitch/Sucrose Non-Fermentable (SWI/SNF) complex, to be associated with lineage plasticity and disease progression in PCa. We posit that it is necessary to study the underlying mechanisms of how the SWI/SNF complex regulates and orchestrates lineage plasticity and other processes that lead to therapy resistance. Further, we have developed a close collaboration with Bob Yauch from Genentech Inc. to identify novel biomarkers and epigenetic therapy approaches for advanced prostate cancer.

This project received support from Roche and the Bern Center of Precision Medicine.

In vitro modeling and genotype-specific therapeutic targeting of DNA repair deficient prostate cancer (Dr. med. Dilara Akhoundova, Medical Oncologist)

Genomic profiling-based personalized treatment of metastatic PCa (mPCa) is a rapidly emerging field of precision oncology. Alterations in DNA damage repair (DDR) genes are present in up to 25% of advanced PCas, more than half of which are found in non-BRCA DDR genes. While inhibitors of poly-ADP-ribose polymerase (PARPis) have demonstrated clinical efficacy in tumors with BRCA1, BRCA2, and a subset of tumors with PALB2 and ATM alterations, highly heterogeneous responses are observed for other non-BRCA DDR alterations. Within this project, we aim to establish and functionally characterize novel in vitro models of non-BRCA PCa DDR deficiency by generating isogenic PCa cell lines deficient for ATM, FANCA and CHEK2. The overall goal of this project is to uncover genotype-specific therapeutic vulnerabilities for ATM, FANCA- and CHEK2-deficient PCa, which currently lack successful molecularly targeted treatment options. Moreover, this project aims to characterize the clinical features and molecular landscape of a unique Swiss cohort of patients with non-BRCA DDR-altered PCas.

The project is supported by the Nuovo-Soldati Foundation for Cancer Research and Kurt und Senta Hermann Foundation.

Molecular characterization and personalized in vitro models for the development of innovative therapeutic strategies for prostate cancer (Dr. med. Dilara Akhoundova, Medical Oncologist).

Molecular characterization of prostate cancer (PCa) primary and metastatic tumors has led to discovery of targetable molecular alterations, with relevant impact on treatment strategy and patient outcome. Still, few molecularly targeted treatment options are available for advanced PCa, and discovery of novel treatment targets and therapeutic sensitivities is needed. Tumor organoids grow indefinitely in vitro and can be cryopreserved in living biobanks, generating functional repositories. These organoids can be employed to in vitro study the molecular mechanisms underlying tumor survival and therapy resistance, as well as tumor therapeutic sensitivities. Currently few in vitro organoid models of advanced PCa are available world-wide. Within this project and employing patient-derived PCa organoids, we aim to improve understanding of the biological mechanisms leading to PCa progression and therapy resistance, as well as identify novel treatment targets and therapeutic sensitivities of advanced PCa.

This project is supported by the ISREC Fondation Recherche Cancer and the Werner und Hedy Berger-Janser Stiftung.