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

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 twohybrid (YTH) system was used to identify a 260 SHCIE 264 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. www.impactjournals.com/oncotarget/

Structures of collagen IV globular domains: insight into associated pathologies, folding and network assembly

“…Intriguingly, only three distinct protomers, 121, 345 and 565 (abbreviated in the following as 121, 345 and 565, respectively), forming three distinct networks, 121, 345 and 121-565, are known to occur in BMs (Boutaud et al, 2000;Borza et al, 2001;Gunwar et al, 1998). Previously unrecognized collagen IV 125 chain combinations have recently been found in various cancer cell lines, which form networks of protomers of 12 chains and 5-chain homoprotomers (Revert et al, 2018). The formation of these novel collagen IV networks is dependent on an exportable protein kinase, the Goodpasture antigen-binding protein (Raya et al, 1999;Revert et al, 2008Revert et al, , 2018, pointing to the involvement of the cellular machinery in regulating the organization of collagen IV networks.…”

“…Previously unrecognized collagen IV 125 chain combinations have recently been found in various cancer cell lines, which form networks of protomers of 12 chains and 5-chain homoprotomers (Revert et al, 2018). The formation of these novel collagen IV networks is dependent on an exportable protein kinase, the Goodpasture antigen-binding protein (Raya et al, 1999;Revert et al, 2008Revert et al, , 2018, pointing to the involvement of the cellular machinery in regulating the organization of collagen IV networks.…”

“…To obtain further insight into collagen IV network assembly and to advance the characterization of the molecular bases of Goodpasture's and Alport's syndromes, we generated various NC1 domains via recombinant technology and used protein crystallography to identify and structurally characterize the oligomers produced by these domains. Using this approach, while attempting to produce crystals of the 345NC1 heterohexamer that predominates in the BM of the kidney, we solved the three-dimensional structure of the recently reported homohexamer of 5NC1 domains (Revert et al, 2018). In addition, we crystallized and determined the structures of the homohexamers spontaneously formed by recombinantly produced 1NC1 and 3NC1 domains.…”

Identification of key genes in prostate cancer gene expression profile by bioinformatics

“…Collagen acts crucial role in the variation of cell phenotype and cell adhesion. The compound T12 is a first‐in‐class candidate drug to cure tumour, as it appears to selectively target the collagen IV of the cancer cell microenvironment (Revert et al, ).…”

In Vitro Vascular Network Modified to Function as Culture Platform and Angiogenic Induction Potential Test for Cancer Cells

“…On the other hand, also the amount of collagen IV has been shown to correlate with tumor burden. This was shown by selectively targeting collagen IV in the cancer cell microenvironment, which was found to reduce tumor burden [47].…”