Netrin and its dependence receptors are mediators of high-grade serous ovarian cancer cell survival

We previously showed that DYRK1A is essential for ovarian cancer spheroid cell survival. DYRK1A regulates transcription by assembling the DREAM repressor complex and also regulates RNA polymerase II. However, the present understanding of how DYRK1A regulates transcription in high-grade serous ovarian cancer (HGSOC) spheroid cells to promote quiescence and survival is lacking. Here we performed GO-CRISPR screens in a panel of HGSOC spheroid cells in combination with transcriptional analyses of DYRK1A deficient spheroid cells. We identified netrin signaling components as essential factors of HGSOC spheroid cell survival. Netrin is well-characterized in axon development but has recently been implicated in other cancer types. We found that knockout of netrin ligands or receptors affects viability of spheroid cells. Netrin ligands and receptors are upregulated in HGSOC cells in suspension conditions. Together, this work suggests that the netrin signaling pathway may be a potential therapeutic target to specifically eliminate spheroid cells in HGSOC and highlights it as an important area requiring further investigation in the context of ovarian cancer. We analyzed three ovarian cancer cell lines: iOvCa147 (GSE150246), OVCAR8, and TOV1946. Each cell line has three replicates for each condition (Adherent (Ad)or Reattached Spheroid (R)). Each condition contains data for Cas9 positive and Cas9 negative samples. The initial plasmid library and GO-CRISPR screen data for iOvCa147 can be found at GSE150246. GO-CRISPR screens for OVCAR8 and TOV1946 were analyzed using TRACS as described in GSE150246. iOvCa147 RNA-seq samples were analyzed using STAR and BEAVR.