Disrupting the immune and drug-privileged microenvironment in pancreas cancer

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PROJECT SUMMARY Pancreatic ductal adenocarcinomas (PDA) develop an intense fibroinflammatory infiltrate that helps promote disease progression and therapeutic resistance. Recent progress has identified essential barriers in this complex microenvironment that impede drug delivery and suppress immunity. These processes include the prohibitive interstitial pressures generated by high concentrations of hyaluronan (HA) complexed with water, dense fibrosis associated with fibrillar collagen deposition, and multiple classes of immunosuppressive and pro-tumorigenic cells such as myeloid-derived suppressor cells and macrophages. The team assembled in this project has made many of the seminal discoveries described above. In addition, we have developed several highly novel and powerful experimental platforms to rigorously interrogate the complex mechanisms and interactions among various compartments in the tumor microenvironment that collectively conspire to promote the survival of pancreas cancers and metastases and thwart treatment. Our overarching hypothesis is that significantly improving survival for PDA patients will require targeting not only the tumor epithelial cell, but also the three compartments that support its oncogenesis: hematopoietic, mesenchymal and extracellular matrix. In the following, we propose to investigate the combination of cytotoxic therapy with stromal disruption and myeloid cell modulations to maximize engagement of anti-tumor immunity and treatment efficacy. We will pursue these investigations in four distinct experimental platforms that offer complementary strengths and mitigate limitations: 1) genetically engineered mouse models (GEMM) of autochthonous PDA; 2) syngeneic allografts; 3) patient-derived xenograft (PDX) systems; and 4) patient-derived organoids (PDO).