title: BCAM and LAMA5 Mediate the Recognition between Tumor Cells and the Endothelium in the Metastatic Spreading of KRAS-Mutant Colorectal Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bartolini
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cardaci
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Lamba
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy. Department of Oncology, University of Turin, Candiolo (Turin), Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Oddo
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchiò
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cassoni
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Carla Azzurra
authors.initials: CA
authors.lastname: Amoreo
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Corti
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Testori
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy. Department of Oncology, University of Turin, Candiolo (Turin), Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.affiliation: University of New Mexico Comprehensive Cancer Center. Albuquerque, New Mexico. Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.affiliation: University of New Mexico Comprehensive Cancer Center. Albuquerque, New Mexico. Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy. Department of Oncology, University of Turin, Candiolo (Turin), Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Corà
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy. Department of Oncology, University of Turin, Candiolo (Turin), Italy. serena.marchio@unito.it federica.dinicolantonio@unito.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo (Turin), Italy. Department of Oncology, University of Turin, Candiolo (Turin), Italy. University of New Mexico Comprehensive Cancer Center. Albuquerque, New Mexico. Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico. serena.marchio@unito.it federica.dinicolantonio@unito.it.
authors.forename: Serena
authors.initials: S
authors.lastname: Marchiò
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology; D064593:Heterografts; D006801:Humans; D007797:Laminin / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008188:Lutheran Blood-Group System / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics*; D019899:Paracrine Communication / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: C090228:BCAM protein, human; D015815:Cell Adhesion Molecules; C117307:KRAS protein, human; D007797:Laminin; D008188:Lutheran Blood-Group System; C097043:laminin alpha5; D016283:Proto-Oncogene Proteins p21(ras)