journal contribution
posted on 2023-03-31, 19:08 authored by Alice Bartolini, Sabrina Cardaci, Simona Lamba, Daniele Oddo, Caterina Marchiò, Paola Cassoni, Carla Azzurra Amoreo, Giorgio Corti, Alessandro Testori, Federico Bussolino, Renata Pasqualini, Wadih Arap, Davide Corà, Federica Di Nicolantonio, Serena Marchiò <p>The supplementary material includes Supplementary Methods, two Supplementary Tables, and six Supplementary Figures Table S1. Complete set of BCAM-mimic peptides. Table S2. Characterization of human CRC cell lines in animal models. Figure S1. Quality control of the phage display experiments: sequencing readout. Figure S2. BCAM protein expression in the complete panel of human hepatic metastases. Figure S3. BCAM protein expression in human primary CRCs. Figure S4. BCAM protein and mRNA expression in all cell lines. Figure S5. Photographic documentation of the experimental hepatic metastasis models. Figure S6. HT-55, DLD-1, LIM1215 and SW-48 cells cannot be reduced to adhesion-functional monocellular suspensions.</p>
Funding
MIUR
Fondazione Piemontese per la Ricerca sul Cancro
Associazione Italiana per la Ricerca sul Cancro
Ministero della Salute
University of Turin
History
ARTICLE 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 = 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colorectal 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 KRAS-mutant 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. ©2016 AACR.
