3D High Density Collagen I Improves Modeling of Metastatic Pancreatic Cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, where most patients (~80%) are diagnosed after metastatic spreading has already occurred, coupled with a dismal overall 5-year survival rate of 13%. Novel therapeutic treatments often show promise in preclinical models then fail when advanced to human clinical trials. This naturally leads one to ask how these preclinical models differ from the clinical disease. PDAC tumors are characterized by a complex tumor microenvironment (TME). Its dense fibrotic stroma is known to contain rich amounts of fibrillar type I collagen, known to be a major driver of metastasis and treatment resistance. Interestingly, most preclinical models used to study the PDAC TME or test promising treatment modalities rely on the injection of tumor cells mixed in basement membrane extract (BME, e.g. Matrigel®) to establish primary tumors. However, BME is composed primarily of laminin and collagen IV while containing no collagen I. Our preliminary results show the importance of incorporating collagen I into PDAC preclinical models. Injecting PDAC cells with 3D high density type I collagen (HDC) generates tumors with significantly more collagen content and extensive metastasis, even in PDAC cells lines that do not normally metastasize in mice. We developed the first successful orthotopic PDAC tumor using 3D HDC in a mouse model, which we utilized to discover a stark contrast in survival between mice in the HDC group versus the BME group. These findings together support our hypothesis that PDAC cells grown in 3D HDC recapitulate the metastatic behavior of human PDAC tumors better than existing models. By accomplishing our aims, we will better understand how the collagen-rich PDAC TME drives metastasis and resistance and engineer a synthetic alternative to better study PDAC preclinical models. Leveraging in vitro and in vivo studies through a multidisciplinary approach, the goals of our proposed project are to (1) demonstrate that HDC co-injection models recapitulate aggressive human PDAC better than traditional BME models; (2) identify how HDC drives collective invasion and metastasis. Because natural matrices contribute to experimental variability, we will (3) develop a synthetic hydrogel substitute comparable to HDC to enable broader implementation in PDAC preclinical research. Our multidisciplinary team, led by a female surgeon and female engineer, will produce a better method of modeling PDAC that more accurately recapitulates metastatic progression and therapeutic resistance. Our approach will provide a more realistic preclinical setting to test new therapeutic strategies and the potential to reveal novel treatment strategies for PDAC.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Novel treatments that show promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC) often fail when translated to human clinical trials. PDAC tumors are notoriously dense with large amounts of high density type I collagen (HDC), whereas most preclinical models involve co-injection of cells in basement membrane extract (BME, e.g. Matrigel®), which contain no type I collagen. In this project, we will demonstrate that co- injection of cells in HDC instead of BME recapitulates aggressive human PDAC better than traditional BME models and develop a synthetic hydrogel substitute, comparable to HDC, to enable broader implementation in PDAC preclinical research.