SMAD4 loss drives chromosomal instability during tumourigenesis via translational reprogramming

Abstract Chromosomal instability (CIN), arising from errors in chromosome segregation during cell division, is a hallmark of cancer. Whilst CIN can result from several mitotic defects, the mechanisms that initiate CIN to drive tumourigenesis remain incompletely understood. Here, we show that loss of SMAD4 reprograms translation to induce CIN, resulting in tumour formation. Multi-omics analysis of tumourigenesis models driven by loss of SMAD4 complemented by functional studies demonstrate that loss of SMAD4 in pre-neoplastic cells leads to dysfunctional mitosis and an altered global translation landscape. We show that CDK11B is translationally downregulated in SMAD4 -\- cells, and re-expression of the mitosis-specific isoform of this protein (CDK11B-p58) rescues the mitotic defects. Analysis of patient tumours reveals a strong correlation between markers of CIN and SMAD4 status, indicating the clinical relevance of this phenotype. Collectively, we reveal a previously unrecognised role for SMAD4 as a gatekeeper for CIN-mediated tumourigenesis via regulation of translation.