title: CD151 promotes α3β1 integrin-dependent organization of carcinoma cell junctions and restrains collective cell invasion.
abstract: Integrins function in collective migration both as major receptors for extracellular matrix and by crosstalk to adherens junctions. Despite extensive research, important questions remain about how integrin signaling mechanisms are integrated into collective migration programs. Tetraspanins form cell surface complexes with a subset of integrins and thus are good candidates for regulating the balance of integrin functional inputs into cell-matrix and cell-cell interactions. For example, tetraspanin CD151 directly associates with α3β1 integrin in carcinoma cells and promotes rapid α3β1-dependent single cell motility, but CD151 also promotes organized adherens junctions and restrains collective carcinoma cell migration on 2D substrates. However, the individual roles of CD151s integrin partners in CD151s pro-junction activity in carcinoma cells were not well understood. Here we find that CD151 promotes organized carcinoma cell junctions via α3β1 integrin, by a mechanism that requires the a3b1 ligand, laminin-332. Loss of CD151 promotes collective 3D invasion and growth in vitro and in vivo, and the enhanced invasion of CD151-silenced cells is α3 integrin dependent, suggesting that CD151 can regulate the balance between α3β1s pro-junction and pro-migratory activities in collective invasion. An analysis of human cancer cases revealed that changes in CD151 expression can be linked to either better or worse clinical outcomes depending on context, including potentially divergent roles for CD151 in different subsets of breast cancer cases. Thus, the role of the CD151-α3β1 complex in carcinoma progression is context dependent, and may depend on the mode of tumor cell invasion.
authors.affiliation: a Department of Biology ; University of Iowa ; Iowa City , IA USA.
authors.forename: Shannin C
authors.initials: SC
authors.lastname: Zevian
authors.affiliation: a Department of Biology ; University of Iowa ; Iowa City , IA USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: a Department of Biology ; University of Iowa ; Iowa City , IA USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Winterwood
authors.affiliation: b Central Microscopy Research Facility, University of Iowa ; Iowa City , IA USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Walters
authors.affiliation: a Department of Biology ; University of Iowa ; Iowa City , IA USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Herndon
authors.affiliation: c Department of Molecular Physiology & Biophysics ; University of Iowa ; Iowa City , IA USA.|d Department of Pathology ; University of Iowa ; Iowa City , IA USA.|e Holden Comprehensive Cancer Center, University of Iowa ; Iowa City , IA USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Henry
authors.affiliation: a Department of Biology ; University of Iowa ; Iowa City , IA USA.|c Department of Molecular Physiology & Biophysics ; University of Iowa ; Iowa City , IA USA.|e Holden Comprehensive Cancer Center, University of Iowa ; Iowa City , IA USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stipp
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D039201:Integrin alpha3beta1 / Q000502:physiology*; D007365:Intercellular Junctions / Q000378:metabolism*; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D060185:Tetraspanin 24 / Q000502:physiology*; D000097794:Kalinin
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D015815:Cell Adhesion Molecules; D039201:Integrin alpha3beta1; D060185:Tetraspanin 24; D000097794:Kalinin; C554715:CD151 protein, human; C513384:CDH1 protein, human
keywords: adherens junctions; cadherin; collective migration; integrin; laminin; tetraspanin