Research Project
10118368
Abstract: Pancreatic ductal adenocarcinoma (PDAC) presents a hostile tumor microenvironment (TME) that is stroma-rich, hypoxic, hypovascular, and with poor perfusion efficiency which can largely contribute to tumor progression/metastasis and the limited delivery efficacy of treatment drugs. Our research is focused on investigating the perivascular heterogeneity in PDAC TME and identify novel mechanisms to reprogram the perivascular signature that will promote vascular functionality. Previously we have shown that perivascular landscape can be modified upon changes of TME and have a profound effect on vascular function. In this grant application, we will investigate dynamic pericyte phenotype in response to the changes of TME. We will utilize both orthotopic and spontaneous mouse models of pancreatic cancer and perform comprehensive pericyte phenotyping at different stages of angiogenic remodeling by employing multispectral imaging of immunolabeled tumors. Previously, Ang2-Tie2 signaling has been implicated in pericyte phenotype; therefore, we will perform genetic ablation of PDGFRb+ pericytes using viral thymidine kinase system (PDGFRb-vTK) which will induce hypoxia and high Ang2 expression. Tumor vasculature will be analyzed to identify the changes. To determine molecular conversion mechanism that is involved in pericyte phenotype, we will utilize mesenchymal stem cells (MSCs), endothelial cells, and pancreatic cancer cells co-culture system. MSCs driven pericytes cultured in a variable environment will be subjected to the molecular profiling. Finally, to evaluate the therapeutic efficacy of pericytes re-investment in combination with chemotherapeutic agents such as gemcitabine (GEM), we will evaluate tumor progression and metastasis on GEMMs of PDAC upon treatment. PDGFRb-vTK-KPC mice will be utilized to deplete immature active PDGFRb+ pericytes then treated with neutralizing anti-Ang2 antibody which will re-invest tumor vasculature with desmin+ mature pericytes in combination with GEM. Tumor progression and metastasis will be monitored to evaluate the efficacy of combinatorial treatment, and changes in perivascular phenotype will be examined by multispectral imaging of immunolabeled tumors. This study will provide insight into pericyte biology regarding the molecular mechanism that governs differential pericyte phenotype as well as innovative approaches to re-purpose chemotherapeutic agents that were previously failed to yield substantial response in patients with PDAC.
