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).
The robust fibroinflammatory stromal response in pancreas cancer creates substantial barriers to treatment but also offers novel therapeutic opportunities. Distinguishing friend from foe amidst this interconnected network of cells and matrix components has not been easy and understanding what to target, when to target it, and for how long, are the major challenges. We propose a series of investigations across highly novel and complementary experimental model systems to investigate and rapidly advance into the clinic the best combinatorial strategies of stromal disruption and immune stimulatory agents to transform the standard-of-care for pancreas cancer.
|Puré, Ellen; Hingorani, Sunil R (2018) Mesenchymal Cell Plasticity and Perfidy in Epithelial Malignancy. Trends Cancer 4:273-277|