Purpose: KRAS mutations confer adverse prognosis to CRC and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets. Experimental Design: A multimodal strategy combining ex-vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS mutant hepatic metastasis from CRC. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n=71). The anti-metastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS mutant CRC cells with TME cells was investigated by adhesion assays. Results: BCAM and LAMA5 were identified as molecular targets within both tumor cells and TME of KRAS mutant hepatic metastasis from CRC, where they were specifically overexpressed. Two BCAM-mimic peptides inhibited KRAS mutant hepatic metastasis in preclinical models. Genetic suppression and biochemical inhibition of either BCAM or LAMA5 impaired adhesion of KRAS mutant CRC cells specifically to endothelial cells while adhesion to pericytes and hepatocytes was unaffected. Conclusions: These data show that the BCAM/LAMA5 system plays a functional role in the metastatic spreading of KRAS mutant CRC by mediating tumor-TME interactions, and as such represents a valuable therapeutic candidate for this large, currently untreatable patient group.
- Received November 2, 2015.
- Revision received March 10, 2016.
- Accepted March 31, 2016.
- Copyright ©2016, American Association for Cancer Research.