Oncogenic drives invasion and maintains metastases in colorectal cancer.

Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the gene. To understand the role of oncogenic in CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic allele ( ) and conditional null alleles of and (iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator of -driven invasiveness. Genetic extinction of resulted in specific elimination of the subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease This faithful CRC model provides genetic evidence that drives CRC invasion and maintenance of metastases.