Transient centrosome loss in cultured prostate epithelial cells induces chromosomal instability to produce an oncogenic genotype that correlates with poor clinical outcomes
Chromosomal instability (CIN) is a hallmark of prostate cancer that strongly correlates with metastatic burden and appears prominently in both primary cancer and metastatic disease. Low Gleason score primary prostate tumors display pervasive centrosome loss, a known mechanistic driver of CIN, that disrupts normal spindle assembly and increases mitotic errors. Previously, we found that transient depletion of centrosomes in immortalized, non-tumorigenic prostate epithelial cells (PrEC) induced a burst of CIN, generating cell lines capable of forming xenograft tumors. Here, we use a multi-omics approach to identify the oncogenic alterations caused by transient centrosome loss. By integrating genomic and transcriptomic data of the prostate lines, we identified a consensus set of focal copy-number variations (CNVs) induced by centrosome loss in cultured cells that are also detectable within a subset of samples from a prostate cancer patient cohort. Using this CNV signature, we were able to derive a unique transcriptomic signature from prostate cancer patient samples that showed strong predictive value for adverse clinical outcomes. In summary, our experimental system uses centrosome loss to promote a punctuated burst of genomic crisis that is characteristic of genome evolution during prostate cancer progression. Consequently, this prostate cancer model produced recurrent structural variations that are detectable in patient samples and associate with worse outcomes. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/653266v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@ac4c9org.highwire.dtl.DTLVardef@fd9961org.highwire.dtl.DTLVardef@160e20corg.highwire.dtl.DTLVardef@198bf0e_HPS_FORMAT_FIGEXP M_FIG C_FIG