CCBIO seminar: Edna Cukierman
Oncogenic synapses; stromal regulators of pancreatic cancer, metabolic support and innate immunosuppression
Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease lacking effective therapies. A major hallmark of PDAC is desmoplasia, characterized by the expansion of cancer-associated fibroblasts (CAFs) and their extracellular matrix, creating a unique microenvironment that limits blood-supplied nutrition and is highly immunosuppressive. The seminar will convey the discrete desmoplastic matrix-informed and integrin-dependent upregulation of a presynaptic protein in CAFs and its postsynaptic binding partner in PDAC cells, which together constitute the bases of a novel “oncogenic synapse”. Using a three-dimensional co-culturing system, based on CAFs isolated from PDAC patients, we observed that oncogenic synapses control key pro-tumorigenic features of CAFs and PDAC cells, in cell autonomous and reciprocal manners. The presynaptic protein in CAFs supports PDAC survival through an oncogenic synapse-mediated nutritional supply that partially depends on glutamate metabolism. The postsynaptic protein controls tumor cell fitness in vivo, likely through the aforesaid metabolic communication with CAFs. Data presented will propose that the intrinsically immunosuppressive CAFs can effectively inhibit NK cell-mediated killing of PDAC cells in a presynaptic protein-dependent manner. Validation in vivo approaches will include the use of patient tissues and a murine PDAC model, which indicated that the ablation of the postsynaptic protein, in PDAC cells, can significantly halt tumor growth. Overall, the seminar will communicate the identification of two new putative targets in different PDAC cellular compartments (i.e., microenvironmental and tumoral) and will highlight the notion that disrupting solely one arm of the newly-recognized “oncogenic synapse” could significantly stunt tumorigenesis.
Chairperson: Donald Gullberg, CCBIO