BCAM and LAMA5 Mediate the Recognition between Tumor Cells and the Endothelium in the Metastatic Spreading of KRAS-Mutant Colorectal Cancer

Abstract

Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, 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 colorectal cancer. 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 ¼ 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colo-rectal cancer 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 colorectal cancer, 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 colorectal cancer cells specifically to endothelial cells, whereas 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 KRASmutant colorectal cancer by mediating tumor-TME interactions and as such represents a valuable therapeutic candidate for this large, currently untreatable patient group. Clin Cancer Res; 22(19); 4923-33. Ó2016 AACR.

Virus-Derived Peptides for Clinical Applications

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Glycophorin-C sialylation regulates Lu/BCAM adhesive capacity during erythrocyte aging

“…1,2 It is expressed as a long (Lu) and a short [Lu(v13)] isoform that differ only in their cytoplasmic tail, which is 59-and 19-amino-acid residues long, respectively. Both isoforms are highly expressed during the early stages of erythropoiesis after which the expression levels strongly decline.…”

Upregulation of BCAM and its sense lncRNA BAN are associated with gastric cancer metastasis and poor prognosis

“…The previous study has shown that BCAM plays a functional role in the metastatic spreading of KRAS‐mutant colorectal cancer. Inhibition of BCAM impaired adhesion of KRAS‐mutant colorectal cancer cells specifically to endothelial cells (Bartolini et al , ). The exact mechanism of BCAM regulating GC invasion and metastasis should be further explored.…”

“…Basal cell adhesion molecule (BCAM), also known as Lutheran, is widely expressed in various tissues and is involved in many biological processes, such as cell adhesion, migration, and invasion (Bartolini et al , ; Campbell et al , ; De Grandis et al , ; El Nemer et al , ; Gauthier et al , ; Hines et al , ; Kikkawa and Miner, ; Kikkawa et al , ; Parsons et al , ). Emerging studies have shown that BCAM plays an important role in tumor progression, including skin tumors, hepatocellular carcinoma, colorectal cancer, and bladder cancer (Bartolini et al , ; Campbell et al , ; Chang et al , ; Drewniok et al , ; Kikkawa et al , ). However, the role of BCAM in GC progression is still unclear.…”