Making vital connections; exploring how desmoplasia gets on pancreatic cancer's nerves
Worldwide Cancer Research
Temple University Health System
Pancreatic ductal adenocarcinoma (PDAC) will soon become the second USA deadliest neoplasia. PDAC features a fibrous stroma, desmoplasia, with low blood/nutritional supply and extensive innervation (neoneurogenesis/axonogenesis) associated with poor prognosis, neuropathy and perineural invasion. The roles of cancer-associated fibroblasts (CAFs) and their self-derived desmoplastic extracellular matrix (D-ECM), in aiding nutritional-deprived tumor survival and neoneurogenesis, which affect PDAC’s onset/progression, are understudied.  Using mRNA from patient’s D-ECM producing CAFs vs. matching normal stellate cells, we discovered a specific glutamatergic presynaptic protein. A simultaneous multiplex immunofluorescent approach validated its overexpression and that of its postsynaptic partner. Increased expression of these proteins is typical in neurological syndromes allied to increased cancer risk. Preliminary data indicated that: D-ECM and CAFs increase both neuron and tumor cell longevity; functional synapses between CAF and other cells are formed; and, CAF-secreted vesicles expressing presynaptic protein engage with PDAC cells, expressing the postsynaptic protein to promote tumor growth.  Hypothesis: PDAC is locally enabled by D-ECM, CAFs, neurons and CAF secreted vesicles in a synapse-like mechanism.  Aim1: Investigate if CAFs support neoneurogenesis and PDAC cells in a synapse-like manner. We will test the functional need for CAF and neural synaptic proteins, as well as downstream enzymes and other proteins, in maintaining high extracellular glutamate levels, posited to sustain neoneurogenesis and PDAC survival under nutritional stress. Our D-ECM system together with gain and loss of function approaches will be used to investigate the synaptic protein roles in these processes.  Aim2: Assess requirement for and level of “pre- and post-synaptic” proteins linked to human PDAC. We will use our multiplex immunofluorescent approach in a well annotated human PDAC cohort to question neoneurogenesis levels associated with quantities and locations of the synaptic pair and question their association with patient outcomes. Vesicles, positive for the pre-synaptic protein, will be probed in matching liquid biopsies.
2.1 Biological and endogenous factors