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High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer. The majority of women are disproportionately diagnosed at an advanced stage (stage III-IV) of the disease when tumours have progressed beyond the ovaries or fallopian tubes and into the peritoneal cavity. Survival rates at late-stage are as low as 25% and chemoresistant disease recurrence is common, affecting up to 90% of patients. Multicellular clusters called spheroids contribute to dormancy, chemoresistance, and metastases and are a major challenge to treatment of HGSOC. Spheroid cells undergo reversible quiescence to evade chemotherapy in a process mediated by the mammalian DREAM complex and its initiating kinase, DYRK1A. Depletion of DYRK1A reduces spheroid cell survival and increases sensitivity to chemotherapy, highlighting it as an attractive therapeutic target. Herein we demonstrate the long-term consequences of DREAM loss in adult mice. DREAM deficient mice do not have proliferative control defects but develop systemic amyloidosis as a result of overexpression of apolipoproteins Apoa1 and Apoa4. Overexpression of Apoa1 and Apo4 were marked with increased B-MYB-MuvB (MMB) and decreased H2AZ deposition within gene bodies. The prolonged latency before developing amyloidosis suggests depriving cells of quiescence is tolerable for short periods of time. To broadly identify genetic vulnerabilities in spheroid cells, we employed an integrated strategy in which we investigated the transcriptional programming and also performed a loss-of-function genome-wide CRISPR screen in HGSOC spheroid cells. Towards this aim, we developed novel bioinformatic tools and methodology to facilitate high-throughput discovery of essential genes and pathways and anticipate these tools will have broad usability in transcriptional and loss-of-function studies. Using these tools, we identified the netrin signaling pathway as an essential mediator of HGSOC spheroid cell survival. Specifically, components of netrin signaling are upregulated in spheroid cells and depletion of netrin ligands or receptors was sufficient to reduce spheroid cell viability. Our work highlights netrin signaling as a potential target for new metastatic ovarian cancer therapies. Taken together, the work presented herein provide more insight into the roles of DREAM and DYRK1A in HGSOC spheroid survival as well as implications of therapeutically targeting this pathway. HGSOC is a very deadly disease and there is an urgent need to develop new therapeutic strategies that can specifically target dormant chemoresistant spheroids in patients to treat or prevent relapse.