Browsing by Subject "pancreatic ductal adenocarcinoma"
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Item Pathway to metastasis: carcinoma dissemination via organized collagen tracks(2017-12) Ray, ArjaA vital part of the metastatic cascade that leads to cancer-related deaths is the initial dissemination of cancer cells from a confined lesion into neighboring tissue by migration and invasion. Breast and pancreatic carcinomas are often associated with increased deposition of collagen-I, which can assemble into aligned fiber tracks in mature breast tumors. Such aligned tracks provide contact guidance cues for directed cancer cell migration and dissemination leading to increased invasion, metastasis and decreased disease-free survival in breast cancer patients. Using multiphoton imaging, we demonstrate that organized collagen architectures develop in the pancreatic ductal adenocarcinoma (PDA) stroma even at the pre-invasive stage with single cells and multicellular clusters interacting with aligned collagen tracks in vivo. Mimicking the collagen patterns with microfabricated substrates, we show that for single cells, aligned architectures induce constrained focal adhesion maturation and associated F-actin alignment, consequently orchestrating anisotropic traction stresses that drive cell orientation and directional migration. While such interactions allow single mesenchymal-like cells to spontaneously “sense” and follow topographic alignment, intercellular interactions within epithelial clusters counteract anisotropic cell-substratum forces, resulting in substantially lower directional response. Indeed, anisotropic cell-substratum interactions from organized periductal collagen may contribute to cell extrusion and dissemination from pre-invasive ductal epithelia in PDA. Such contact guided spreading of cancer cells may be inhibited by dismantling the fiber architecture, diminishing its density or by abrogating cell-ECM interactions. To validate our findings in 3D we engineered novel in vitro substrates using a simple method to align 3D collagen gels by guided cellular compaction, to produce highly aligned, acellular collagen constructs as a controlled microenvironment in vitro. Additionally, we integrated the aligned collagen matrices to cell dense tumor-like plugs, allowing tracking of the temporal evolution of the advancing invasion fronts over several days. Live cell imaging and analysis of 3D cell migration revealed profoundly enhanced motility in aligned collagen matrices for the putative cancer stem cell subpopulation. Heterogeneity in cell migration behavior was also observed between cells at the leading edge and those within the tumor boundary, thus demonstrating the versatility of these platforms in capturing the dynamics of contact guided carcinoma dissemination.Item The role of bone marrow-derived progenitor cells in pancreatic cancer(2021-12) Edwards, RachelPancreatic ductal adenocarcinoma (PDA) is the most common type of pancreatic cancer, and it has an extremely poor prognosis for patients. PDA is distinct from many other cancer types in that it has a robust desmoplastic reaction deposited by the large number of pancreatic stellate cells (PSC) present within the tumor microenvironment (TME). In the human disease, the number of PSC can be so high that the number of quiescent, resident PSC present in the normal pancreas could not undergo enough rounds of proliferation without becoming a transformed cell type to result in the number of activated PSC observed in the tumor. Review articles have posited that mesenchymal stem cells (MSC) are one source of these cells for nearly a decade even though, to our knowledge, no one has conclusively shown this to be true. In this work, we set out to show this to be true, but our findings largely contradicted this hypothesis. We attempted to show that MSC home to PDA through multiple different methods, which are described in the following chapters. A bone marrow transplantation (BMT) method was employed to transplant two distinctly labelled stem cell populations in our GEMM of pancreatic cancer with Kras, p53, and Cre mutations (KPC). The results were inconclusive for our hypothesis because we found that MSC could not be transplanted into and reconstitute the mesenchymal niche in the bone marrow in the same manner as hematopoietic stem cells (HSC). A parabiosis surgical model was used to connect the circulation between a genetically engineered mouse model (GEMM) with fluorescently labelled MSC in the bone marrow and our KPC model. This was done to observe homing from resident, labelled MSC to overcome the limitations of transplanting MSC. We were unable to observe any signs of fluorescent MSC in the pancreas of diseased mice. Other subcutaneous (SQ) and injection models were used to compare our models and results with previous literature to gain a better understanding of the limitations of each system. We found that artifacts of less physiologically relevant models of disease may have contributed to the misunderstanding of pancreas cancer biology for over a decade.