Oncogenic Kras drives invasion and maintains metastases in colorectal cancer

Abstract

Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the KRAS gene. To understand the role of oncogenic KRAS in CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic Kras allele (Kras mut ) and conditional null alleles of Apc and Trp53 (iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the Kras mut allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Kras mut signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator of Kras mut -driven invasiveness. Genetic extinction of Kras mut resulted in specific elimination of the Kras mut subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease. This faithful CRC model provides genetic evidence that Kras mut drives CRC invasion and maintenance of metastases.

No back seat for a progression event—K-RAS as a therapeutic target in CRC

“…In this vein, the Boutin et al (2017) study is more similar to a 2010 study in which Feldser et al (2010) re-expressed P53 in K-RAS mutant, P53-null lung adenocarcinomas, selectively causing senescence in adenocarcinomas while sparing adenomas. While the Boutin et al (2017) and Feldser et al (2010) experiments have similar outcomes (reversion of adenocarcinomas to adenomas), the mechanisms are quite distinct. In CRC, adenocarcinoma regression is a genotype-specific phenomenon (apoptotic loss of K-RAS MUT cells or retention of K-RAS WT cells), while, in the lung, adenocarcinoma regression is dependent on tumor state (clearance of senescent adenocarcinoma or retention of adenoma) (Fig.…”

“…Unlike these prior studies, which investigated initiating oncogenes, K-RAS activation in CRC is a progression event (Haigis et al 2008). In this vein, the Boutin et al (2017) study is more similar to a 2010 study in which Feldser et al (2010) re-expressed P53 in K-RAS mutant, P53-null lung adenocarcinomas, selectively causing senescence in adenocarcinomas while sparing adenomas. While the Boutin et al (2017) and Feldser et al (2010) experiments have similar outcomes (reversion of adenocarcinomas to adenomas), the mechanisms are quite distinct.…”

“…More than 40% of CRCs harbor an activating missense KRAS mutation, but how mutant K-RAS contributes to CRC progression and whether aberrant K-RAS activity is required for tumor maintenance remain unclear. The study by Boutin et al (2017) provides new insights into these important questions.…”

“…For example, GEMMs were used to demonstrate that K-RAS activation in the context of APC mutant colonic epithelium is sufficient to induce dysplastic adenocarcinomas, as predicted by the Fearon and Vogelstein model (Haigis et al 2008). In their new study, Boutin et al (2017) have created a CRC mouse model in which mutations in APC, P53, and KRAS are spatially and temporally regulated. This model improves on prior models in that expression of mutationally activated K-RAS G12D is independently controlled, mosaic, and reversible, allowing the investigators to study the function of K-RAS in CRC maintenance.…”

“…This model improves on prior models in that expression of mutationally activated K-RAS G12D is independently controlled, mosaic, and reversible, allowing the investigators to study the function of K-RAS in CRC maintenance. In the Boutin et al (2017) model, loss of oncogenic K-RAS expression induces apoptosis in both primary and metastatic adenocarcinomas. Primary tumors do not regress completely, however, since adenomatous tissues that failed to express mutant K-RAS in the first place are spared from apoptosis ( Fig.…”