The link between centrosome defects and cancer unveiled by CROCC deficiency in rhabdoid colorectal cancer

The century-old hypothesis on the role of centrosome in cancer remains unresolved. We show that reduced dosage of CROCC, a centrosomal-linker component required for centrosome cohesion and separation, due to mutation or allelic loss at 1p36.13 results in impaired centrosome phenotypes and monopolar mitotic forms characterizing a lethal subset of human colorectal cancers with rhabdoid phenotype. Interfering with CROCC in near-diploid colon cancer cells disrupts bipolar mitotic spindle architecture, and causes unequal DNA segregation errors to daughter cells resulting in a highly aggressive rhabdoid-like phenotype in vitro. Conversely, CROCC restoration in a metastatic cellular model harboring 1p36.13 deletion results in correction of centrosome segregation errors and cell death, revealing a mechanism of tolerance to gross mitotic errors and tetraploidization, two hallmarks of chromosomal instability. Together, our data shed light on a previously unknown link between centrosome cohesion apparatus and lethal cancer phenotypes providing new insight into pathways underlying genome instability.