Oncotarget

Research Papers:

Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden

Fernando Revert, Francisco Revert-Ros, Raül Blasco, Aida Artigot, Ernesto López-Pascual, Roberto Gozalbo-Rovira, Ignacio Ventura, Elain Gutiérrez-Carbonell, Nuria Roda, Daniel Ruíz-Sanchis, Jerónimo Forteza, Javier Alcácer, Alejandra Pérez-Sastre, Ana Díaz, Enrique Pérez-Payá, Juan F. Sanz-Cervera and Juan Saus _

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Oncotarget. 2018; 9:11020-11045. https://doi.org/10.18632/oncotarget.24280

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Abstract

Fernando Revert1,2, Francisco Revert-Ros1,2, Raül Blasco1,3, Aida Artigot1, Ernesto López-Pascual1,2, Roberto Gozalbo-Rovira1,8, Ignacio Ventura1,2,9, Elain Gutiérrez-Carbonell1,10, Nuria Roda4, Daniel Ruíz-Sanchis1, Jerónimo Forteza5, Javier Alcácer6, Alejandra Pérez-Sastre1,2,11, Ana Díaz7, Enrique Pérez-Payá4, Juan F. Sanz-Cervera3 and Juan Saus1,2,4

1FibroStatin, Parc Científic Universitat de València, Paterna 46980, Spain

2Centro de Investigación Príncipe Felipe, Valencia 46012, Spain

3Departament de Química Orgànica, Universitat de València, Burjassot 46100, Spain

4Departament de Bioquímica i Biologia Molecular, Universitat de València, Burjassot 46100, Spain

5Instituto Valenciano de Patología of Universidad Católica de Valencia, Centro de Investigación Príncipe Felipe, Valencia 46012, Spain

6Anatomía Patológica, Hospital Quirónsalud de Valencia, Valencia 46010, Spain

7Unitat Central d'investigació en Medicina, Facultat de Medicina i Odontologia, Universitat de València, Valencia 46010, Spain

8Present address: Departament de Microbiologia i Ecologia, Facultat de Medicina i Odontologia, Universitat de València, Valencia 46010, Spain

9Present address: Universidad Católica de Valencia, Valencia 46001, Spain

10Present address: Sciex Spain, Alcobendas, Madrid 28108, Spain

11Present address: Sistemas Genómicos, Paterna 46980, Spain

Correspondence to:

Juan Saus, email: juan.saus@uv.es

Keywords: GPBP; collagen IV; EMT; drug-resistant cancer; tumor microenvironment

Received: July 13, 2017     Accepted: January 03, 2018     Published: January 19, 2018

ABSTRACT

Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast two-hybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2''-yl]propionic acid, or T12, specifically targets mesenchymal GPBP and disturbs its multimerization without affecting kinase catalytic site. Importantly, T12 reduces growth and metastases of tumors populated by EMT phenotypes. Moreover, low-dose doxorubicin sensitizes epithelial cancer precursor cells to T12, thereby further reducing tumor load. Given that T12 targets the pathogenic mesenchymal GPBP, it does not bind significantly to normal tissues and therapeutic dosing was not associated with toxicity. T12 is a first-in-class drug candidate to treat cancer by selectively targeting the collagen IV of the tumor cell microenvironment.


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