Year: 2016
Type: article
Abstract: Pancreatic ductal adenocarcinomas are highly malignant cancers, characterized by extensive invasion into surrounding tissues, metastasis to distant organs at a very early stage, and a limited response to therapy. One of the main features of pancreatic ductal adenocarcinomas is desmoplasia, which leads to extensive deposition of collagen I. We have demonstrated that collagen I can induce epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. A hallmark of EMT is an increase in the expression of a mesenchymal cadherin, N-cadherin. Our previous studies have shown that up-regulation of N-cadherin can promote tumor cell invasion and that collagen I-induced EMT is through two collagen receptors α2β1 integrin and discoidin domain receptor 1 (DDR1). DDR1 is a receptor tyrosine kinase widely expressed during embryonic development and in many adult tissues. It is also highly expressed in many different cancers. However, the role of DDR1 in pancreatic cancer is largely unknown. In the collagen Iinduced up-regulation of N-cadherin signaling pathway, we have shown that Proline-rich tyrosine kinase 2 (Pyk2) is downstream of DDR1. In this study, we found that isoform b of DDR1 is responsible for collagen I-induced up-regulation of N-cadherin and that it is Tyrosine513 of DDR1b that is involved. Knocking down Shc1, which binds to Tyrosine513 on DDR1b, eliminates N-cadherin up-regulation. We also found that the signaling is mediated by the interaction between the central domain of Shc1 and the proline-rich region of Pyk2. Taken together, these data illustrate that DDR1b, and not DDR1a, specifically mediates collagen Iinduced N-cadherin up-regulation and that Shc1 is involved in this process.
Source: DigitalCommons@UNMC
Author: Huocong Huang
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: University of Southern California, University of Nebraska Medical Center, University of Connecticut, McGill University, Institut National de la Santé et de la Recherche Médicale, National Institutes of Health, University of North Carolina at Chapel Hill, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1594129926, Pancreatic Tumor Micro-environment Network, Aspects of Cadherin/Catenin Complexes, G4472133864, Nebraska Center for Cellular Signaling, Exploiting Novel Pathways to Treat Pancreatic Cancer, G6099097669, SPORE in Pancreatic Cancer, Early Diagnosis of Pancreatic Cancer, Buffett Cancer Center Support Grant
OpenAlex ID: W2589071276