Csig-15. ptn-ptprz1 signaling mediates tumor-normal crosstalk in glioblastoma

Glioblastoma (GBM) is the most devastating form of brain cancer with poor patient prognosis and high recurrence. An increasing body of literature suggests crosstalk between tumor and its surroundings, both molding the immune microenvironment and forming functional synapses with neighboring normal cells. Despite the high intra-tumoral and inter-patient heterogeneity, we have discovered PTN-PTPRZ1 signaling as the most significant and preserved communication pathway between GBM cells and their immediate neighboring cells. Through a novel tumor transplantation protocol onto cortical organoids, which are human embryonic stem cell-derived aggregates that faithfully mimic the human brain, we have seen evidence of tumor-normal crosstalk where PTN-PTPRZ1 is a key signaling axis. We hypothesize that PTN-PTPRZ1 signaling is pivotal to tumor growth and invasion, which ultimately leads to recurrence. Modulating PTN and/or PTPRZ1 levels on the cortical organoids via shRNA affects PTN and/or PTPRZ1 expression on the tumors, suggesting dynamic communication between tumor and normal cells via PTN-PTPRZ1 signaling. During the process of generating PTN knockdown cortical organoids, we have additionally discovered a pivotal role for PTN in the very early stages of cortical development. PTN and PTPRZ1 are signature markers of the outer radial glia in the developing human brain, which are absent in mouse models where the majority of PTN biology has been studied. By supplementing exogenous PTN to PTN knockdown organoids and withdrawing it at various timepoints, we have identified drastic phenotypes of neuron and radial glia survival and cell fate specification. With cortical organoids, we can interrogate the role of PTN in the early stages of neurodevelopment via a human-derived system.