Ended Projects

Elucidating the role of the metastatic niche (Dr. Alison Ferguson, Postdoc)

Through in vitro models, we aim to characterize the co-evolution of the tumor microenvironment in complex organoid models recapitulating the metastatic niche. With our extensive cohort of patient-derived tumor organoids, we are developing first-of-its kind in vitro models of prostate cancer metastasis in both the brain and liver. These models are being further utilized to investigate biomarkers and driver mutations of site-specific metastasis. Modelling the metastatic niche in vitro is an innovative approach facilitating a better understanding of tumor evolution, therapeutic resistance and will uncover novel therapeutic targets.

Data analysis pipelines

The SOCIBP genomic pipeline is a collection of containerized analysis modules capable of processing genomic data from different sequencing platforms, panels, and sample types that are commonly used in cancer genomics, either in clinical or research settings (Figure). The concept of the SOCIBP pipeline is based on current best practices in genomic research and data reproducibility, including the ICGC ARGO best practices for scientific workflow development. Priorities for us at this stage are 1) portability (easy deployment of the modules on different servers regardless of their architecture or job scheduler) and 2) reproducibility (processes will run in the same way and produce the same results from the same input on any computing platform). Currently, the SOCIBP pipeline has been deployed and is being tested on the LeoMed server (Zurich) and the Insel HPC (Bern).

Over the past 12 months, we have made substantial improvements to variant filtering for our whole-exome data analysis and amplicon-based panel sequencing data analysis pipelines. We have also added several value-added analysis modules, especially for the whole-exome data analysis pipeline. These modules include the detection of microsatellite instability and homologous recombination deficiency, the detection of allele-specific copy number alterations, clonality and tumor mutational signatures. For the amplicon-based panel sequencing data analysis pipelines, we have also added a new module to detect fusion from RNA panel sequencing data.

Modularity is the main characteristic of the SOCIBP pipeline. This facilitates a more efficient development of its components and deployment of only the modules needed for specific analyses, depending on data types and goals. Currently, the SOCIBP modules are run as independent versioned tools, which is sufficient for expert usage. Our next goal is to develop an umbrella wrapper (written in nextflow and/or snakemake) that will be versioned, and would handle the execution of each module or a series of modules. This would enable much easier usage of the SOCIBP pipeline and would facilitate its adoption in hospitals or research centers.

In summary, this pipeline could be useful to help bridge many complex sources of genomic data (whole genome, whole exome, targeted exomes, targeted amplicon-based panels).

Swiss Oncology and Cancer Immunology Breakthrough Platform (SOCIBP) for Precision Oncology.

This project lead by Prof. Rubin with co-leads Holger Moch (UHZ), George Coukos (CHUV/UNIL), and Gunnar Rätsch (ETHZ) will provide both important new tools for the Swiss and international research community, as well as addressing tumor cell resistance, one of the greatest unmet challenges in immunology-based therapies for cancer. The project will create a shareable research structure across Switzerland to enable precision oncology trials for years to come.

Funded by the Swiss government via SPHN/PHRT

This project would be highly relevant to helping integrating clinical and research genomics and transcriptomics data to a uniform research setting. The work is on-going and part of ICGC-ARGO.

Towards a precision therapy for Speckle-type POZ protein (SOP) mutant prostate cancer

This project is funded by the Swiss Krebsliga Association in collaboration with Ruedi Aebersold’s laboratory (ETHZ). The focus of this study is to understand the downstream effectors of SPOP, recurrently mutated in 10% of primary prostate cancer patients, through targeted proteomics, and to help develop clinical biomarkers. Our overarching hypothesis is that SPOP mutant prostate cancer will respond distinctly to targeted therapy due to its inherent vulnerabilities. Other areas of SPOP biology are supported by an NCI grant in its 9^th year.

Role of m6A methylation in post-transcriptional regulation and prostate cancer disease progression

m6A methylation of mRNAs can alter RNA stability, protein translation efficiency, and patterns of alternative splicing. The aim of the project is to investigate the frequency of m6A in prostate cancer and its functional consequences for the progression of the disease. It is the first study to examine how prostate cancer utilises this alternative molecular mechanism to regulate gene and protein expression. It will provide valuable fundamental research that will contribute to a better understanding of the molecular functioning of prostate cancer.