ERC FUNDED PROJECTS

Aneuploidy, an imbalanced number of chromosomes or chromosome arms, is a distinct feature of cancer. Recent years have seen conceptual, methodological and technical advances in the field of cancer aneuploidy research, but we are just beginning to scratch the surface of the underlying biology, and the potential vulnerabilities of aneuploid cancer cells remain under-explored. Cancer aneuploidy is therefore a biological enigma and a missed opportunity for cancer therapy. Identifying the “Achilles heels” of aneuploidy remains a holy grail of cancer research. However, current models of aneuploidy fail to fully recapitulate the cellular consequences of aneuploidy in cancer, thus compromising the identification of aneuploidy-induced cellular vulnerabilities. The time is ripe to tackle cancer aneuploidy with state-of-the-art genomic and functional approaches. In this project, I propose to address the following key questions: 1) What forces shape the evolution of aneuploidy in tumors? We will integrate in silico analyses of clinical data, in vitro modeling in isogenic human cell lines, and in vivo experiments in mice, to elucidate how various cellular contexts shape the tumor aneuploidy landscape. 2) What cellular vulnerabilities are induced by aneuploidy? We will combine isogenic cell lines with large-scale genetic and chemical perturbation screens, in order to identify, validate, and mechanistically dissect vulnerabilities induced by aneuploidy in human cancer cells. These research aims fall well within my unique expertise. I mapped various aneuploidy landscapes and developed innovative experimental and computational tools for studying cancer aneuploidy. A successful completion of the project will shed light on the context-dependent cellular consequences of aneuploidy in cancer and provide proof-of-concept for its potential targeting. Ultimately, identifying aneuploidy-specific vulnerabilities will pave the way for the therapeutic exploitation of this hallmark of cancer.

1 612 500 €

Start date: 2021-10-01, End date: 2026-09-30

Cancer genomics has revolutionized cancer research by systematic mapping of oncogenic genetic alterations of genes, yet oncogenic epigenetic alterations of regulatory elements away from genes remain elusive. I recently demonstrated that aberrant DNA methylation of CTCF binding sites perturbs chromosomal topology in IDH-mutant glioma and SDH-deficient gastrointestinal stromal tumors (GISTs). Loss of CTCF binding at the boundary between two topologically associating domains disrupts their insulation, leading to oncogene activation. This groundbreaking model links metabolic, epigenetic and topological alterations and demonstrates that they can drive oncogenesis. Aberrant DNA methylation is common in many tumors and therefore epigenetic CTCF disruption may play a role in other cancers, but this has not been studied to date. Prompted by my findings, recent advances in genome-wide characterization methods and newly available large-scale data, I now propose to systematically uncover the rules of regulation of DNA methylation at CTCF binding sites, and how its disruption in cancer leads to epigenetic heterogeneity and drives oncogenesis. To achieve that, we will develop new statistical models to systematically uncover the rules of regulation of DNA methylation at CTCF binding sites and its impact on topology (Aim 1); uncover mechanisms of epigenetic topological alterations and their role in cancer (Aim 2); and develop computational tools to study intratumor epigenetic heterogeneity to investigate the interplay between different subclones (Aim 3). Taken together, this research program will facilitate a systematic understanding of epigenetic topological alterations and their role in cancer. These are critical goals for the field in order to understand the events that drive cancer, to discover new biomarkers, dependencies and therapeutic strategies, and to inform epigenetic and other personalized therapies.

1 500 000 €

Start date: 2021-02-01, End date: 2026-01-31

In 1914 Theodor Boveri described abnormal chromosome counts in cancer cells and speculated that these alterations are the driving force of cancer. Almost 100 years later it became clear that somatic copy number alterations (SCNAs) are one of the most striking characteristics of cancer genomes. SCNAs comprise deletions and amplifications of whole chromosome arms and therefore alter the expression patterns of several hundred genes simultaneously. These alterations show defined patterns suggesting selective pressure, and thus likely contain multiple driver genes, which can shape several tumorigenic properties. Therefore, studying how these events contribute to tumor development will be fundamental to understand cancer biology and develop targeted cancer therapies. However, whereas the function of recurrently mutated driver genes can be readily assessed, studying SCNAs remains challenging so far. This project will overcome these limitations by combining our unique ability to model liver cancer in vivo and in vitro with innovative CRISPR-based genomic engineering technologies. First, we will generate large chromosomal deletions in murine livers and human-derived liver organoids by CRISPR technologies and assess their functional role in cancer development. Furthermore, synthetic lethal interactions generated by these deletions will be evaluated on their therapeutic potential. Additionally, driver genes and driver gene-combinations of amplified chromosomal regions will be investigated using a novel CRISPR/Cas9-based mouse model for endogenous gene activation and chromosome engineering. Finally, we will exploit a novel concept for targeting cancer cells with specific amplifications. Our unique approach will for the first time systematically investigate the functional role of SCNAs in tumor pathobiology, identify new therapeutic strategies specifically tailored for individual SCNAs, and will therefore have high impact for future efforts to understand and combat cancer.

1 500 000 €

Start date: 2021-01-01, End date: 2025-12-31

Immunotherapies targeting immune regulators are revolutionizing cancer treatment, most prominently in melanoma, but only for a subset of patients. While it is known that the immune tumor microenvironment (iTME) plays a vital role in this process, there is limited understanding on how distinct tumor, immune and stroma cells interact as a system to collectively define progression and response to treatment, and there is no biomarker to predict patient response. Tumors are spatially organized ecosystems that are comprised of distinct cell types, each of which can assume a variety of phenotypes defined by coexpression of multiple proteins. To underscore this complexity, and move beyond single cells to multicellular interactions, it is essential to interrogate cellular expression patterns within their native context in the tissue. We have recently pioneered MIBI-TOF (Multiplexed Ion Beam Imaging by Time of Flight), a novel platform that enables simultaneous imaging of forty proteins within intact tissue sections at subcellular resolution. We propose to (1) Use MIBI-TOF to chart the iTME in dozens of clinical samples from melanoma patients and delineate its function in response to different immunotherapies. (2) Profile murine melanoma tumors to elucidate genetic and temporal mechanisms that drive iTME organization in vivo. (3) Develop new experimental tools for tracing and barcoding thousands of cells to decouple the effects of tumor genetics and the immune microenvironment on tumor organization and clonal dynamics. (4) Develop machine-learning-based algorithms to analyze this novel data and facilitate accessibility of the scientific community to high-dimensional imaging to study human malignancies. This proposal applies state-of-the-art imaging technology and computation to unravel design principles of the iTME in melanoma, with a grand goal to reveal basic principles in tumor immunology and improve treatment and diagnostics.

1 613 750 €

Start date: 2021-01-01, End date: 2025-12-31