Human organoid tumor transplantation identifies functional glioblastoma-microenvironment communication mediated by PTPRZ1

Glioblastoma is the most aggressive and deadly form of brain cancer. Here, we leverage our human organoid tumor transplantation (HOTT) co-culture system to explore how extrinsic cues modulate glioblastoma cell types and behavior. HOTT recapitulates core features of major patient tumor cell types and key aspects of neural cell-enriched tumor microenvironment (nTME) gene programs. Our exploration of patient TME interactions preserved in HOTT highlights four receptor-ligand interactions of interest. We knock down all four of these genes in the HOTT microenvironment. We observe that knocking down nTME PTPRZ1, a receptor tyrosine phosphatase implicated in cancer cell migration, results in an increased fraction of mesenchymal cells, enrichment of epithelial-to-mesenchymal gene programs, and an elevated tumor microtube length in co-cultured primary patient tumors. This phenotype is not mediated by PTPRZ1’s catalytic activity, suggesting a mechanism of tumor cell fate driven by nTME PTPRZ1, highlighting the strengths of the HOTT system.