Bioengineering and biomechanical approaches for pancreatic cancer

Abstract

Pancreatic cancer is the fourth-leading cause of cancer related mortality and is predicted to be the second leading cause of cancer death by 2030. A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is dense fibrotic stroma surrounding the tumor, composed of extracellular matrix (ECM) and cells such as myofibroblasts. The properties of this stroma and functional contribution to carcinogenesis and disease progression has been the subject of intense focus in the past decade; yet, the role of mechanobiology in modulating the phenotype of immune cells in the tumor microenvironment remains to be elucidated. Although a lack of understanding PDAC etiology and progression limits effective treatments that can be deployed by clinicians, current methods of diagnosing PDAC likely are insufficient even if such treatments exist, especially if there is a narrow early window for drug efficacy. Recently, however, extracellular vesicles have emerged as powerful circulating blood biomarkers, thus paving the way for a new era of non-invasive cancer diagnostics. However, currently the process of extracellular vesicle isolation and detection is not only highly inefficient, but also technically challenging. This thesis describes bioengineering tools and biomechanical investigations of pancreatic cancer. In Chapter 2, the biomechanical phenotype of macrophages is studied in context of a stromal modulation agent, the chemotherapeutic drug tamoxifen. Tamoxifen was found to regulate macrophage focal adhesion dynamics, cytoskeletal activity, migratory behavior, and expression of TLR4. In Chapter 3, a novel microfluidic device was modeled and built to determine cell adhesion strength with potential applications to investigate regulation of focal adhesion structure by candidate drugs. Chapter 4 describes the development of methods and devices for isolation and detection of extracellular vesicles using acoustophoresis and a graphene field effect transistor, respectively. Such tools and perspectives could serve to detect PDAC earlier as well as identify and test new therapies.