Abstract
Collagen XV (COLXV) is a secreted non-fibrillar collagen found within basement membrane (BM) zones of the extracellular matrix (ECM). Its ability to alter cellular growth in vitro and to reduce tumor burden and increase survival in vivo support a role as a tumor suppressor. Loss of COLXV during the progression of several aggressive cancers precedes basement membrane invasion and metastasis. The resultant lack of COLXV subjacent to the basement membrane and subsequent loss of its interactions with other proteins in this zone may directly impact tumor progression. Here we show that COLXV significantly reduces invasion of pancreatic adenocarcinoma cells through a collagen I (COLI) matrix. Moreover, we demonstrate that epithelial to mesenchymal transition (EMT) in these cells, which is recapitulated in vitro by cell scattering on a COLI substrate, is inhibited by over-expression of COLXV. We identify critical collagen-binding surface receptors on the tumor cells, including the discoidin domain receptor 1 (DDR1) and E-Cadherin (E-Cad), which interact with COLXV and appear to mediate its function. In the presence of COLXV, the intracellular redistribution of E-Cad from the cell periphery, which is associated with COLI-activated EMT, is inhibited and concurrently, DDR1 signaling is suppressed. Furthermore, continuous exposure of the pancreatic adenocarcinoma cells to high levels of COLXV suppresses endogenous levels of N-Cadherin (N-Cad). These data reveal a novel mechanism whereby COLXV can function as a tumor suppressor in the basement membrane zone.
Highlights
Unlike organized fibrillar collagens, which are abundant in the extracellular matrix (ECM), non-fibrillar collagens have only recently been associated with early events in cancer progression
Collagen XV (COLXV) is distinct from the many fibrillar collagens that are involved in cancer progression due to its unique location within basement membrane zones, and its flexible pretzel-like structure, in contrast to the rigid fibrillar collagens such as collagen I (COLI)
We show that discoidin domain receptor 1 (DDR1) and E-Cad interact with COLXV and that the presence of COLXV in the extracellular milieu inhibits COLI - mediated DDR1 signaling
Summary
Unlike organized fibrillar collagens, which are abundant in the extracellular matrix (ECM), non-fibrillar collagens have only recently been associated with early events in cancer progression. COLXV is a secreted 1388 amino acid protein localized within the outermost lamina densa in basement membrane zones of the ECM [8]. COLXV null mice (Col151a 2/2) show aberrant matrix biology in multiple organs, implicating a role for this protein in tissue remodeling events, protein interactions, and molecular signaling [14,15]. COLXV is distinct from the many fibrillar collagens that are involved in cancer progression due to its unique location within basement membrane zones (the first areas compromised in tumor extravagation), and its flexible pretzel-like structure, in contrast to the rigid fibrillar collagens such as collagen I (COLI). During cancer progression, fibrillar collagens contribute to characteristic fibrosis while non-fibrillar COLXV is lost prior to metastasis. The associated loss of structural integrity of the basement membrane zone likely contributes to poor survival since it may facilitate invasion, initially through the basement membrane, leading to distal metastases
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