Collagen Signaling in Pancreatic Cancer

Abstract Pancreatic Ductal Adenocarcinoma (PDA) is the 3rd most common cause of cancer death in the United States. One of the primary pathological features of PDA is the dense network of fibrillar collagens (COLs), including COL1 and COL11, both of which have been shown to be associated with PDA progression. Collagens signal via specific receptors on the surface of PDA cells, of which the Discoidin Domain Receptor 1 (DDR1) is a unique collagen receptor tyrosine kinase (RTK). We have found that ablation of DDR1 inhibits disease progression and metastasis whereas overexpression enhances these processes in mouse models of PDA, suggesting that DDR1 is a major promoter of malignancy. The signaling networks activated by DDR in response to COLs remain elusive. Using an innovative approach to simultaneously map the phospho-catalytic profile of multiple kinases in cells or tissues we discovered that tumor xenografts of PDA cells expressing DDR1 embedded within in a COL1 scaffold display a unique profile of activated kinases, which represent new DDR1-initiated signaling pathways revealing potentially druggable vulnerabilities to target these highly fibrotic tumors. We have also found that COL5 and COL11, fibrillar collagens associated with poor outcome in PDA, actives DDR1 to an almost 20-fold greater level that COL1, its most commonly examine ligand. In this proposal, we will focus on how 1) the COL11/DDR1 signaling axis promotes PDA metastasis in vitro and in vivo 2) how distinct COLs differentially activate DDR1 3) identify druggable vulnerabilities associated with COL5/11- DDR1 signaling to develop for future treatments of these highly fibrotic tumors.