Deconstructing and targeting aneuploidy in human cancer - Resubmission - 1

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Summary Aneuploidy—the presence of chromosome gains and losses—is very rare in normal tissues but occurs in more than 80% of human tumors, especially in solid tumors. A high level of aneuploidy in tumors correlates with higher- grade disease, tumor progression, and resistance to therapy. Whether and how aneuploidy contributes to formation and progression of human tumors is not well understood. Whereas genomic and clinical studies in cancer patients suggest that aneuploidy drives tumorigenesis, experimental studies in mouse models and in vitro systems has so far yielded conflicting data on the role of aneuploidy in tumors. Human tumors are often specifically associated with either increases or decreases in the number of specific chromosome(s). One of the main obstacles to progress has been the technical limitation of not being able to engineer the ‘right’ type of aneuploidy in the ‘right’ cell type. Our ultimate goal is to dissect whether and how aneuploidy contributes to initiation and progression or human tumors. Our first objective here is to generate cellular models that faithfully recapitulate the aneuploidy patterns found in tumors in order to study how aneuploidy affects the pathobiology of tumor cells (their ability to grow in vitro or in vivo, to evade cell death pathways, to survive cellular stress and to regulate transcription and translation). Our second objective is to uncover vulnerabilities and synthetic lethal interactions potentially associated with the aneuploid state. The outcomes of the proposed project will represent the foundation to achieve the long-term goal of our lab, which is to develop a better understanding of the causes and consequences of aneuploidy in human tumors in order to uncover aneuploidy-associated biomarkers and therapeutic targets. To accomplish this goal, we will first use a panel of newly generated human cells containing different degrees and types of aneuploidy to compare diploid and aneuploid cells for several tumor-related cellular phenotypes both in vitro and in vivo. Secondly, we will adopt a systematic approach to identify genes and pathways that when blocked, inhibit proliferation and survival of aneuploid tumor cells but not normal cells. Third, we will perform a protein and phospho-protein analysis mainly of colorectal tumor patients’ samples to dissect the consequences of aneuploidy at the level of protein stability and pathway regulation. Our results will fill an important gap of knowledge in our current understanding of how aneuploidy evolves during tumorigenesis and how we might take advantage of this knowledge to improve patient outcomes.