LAUSR

Glioblastoma is a lethal brain tumor with a high degree of heterogeneity and resistance to therapy. The lack of genetic tracing approaches to selectively identify tumor states and fate transitions limited our understanding of tumor homeostasis. By translating glioblastoma subtype signatures into synthetic genetic tracing cassettes, we investigated tumor heterogeneity at cellular and molecular level, in vitro and in vivo. Synthetic genetic tracing demonstrated that proneural glioblastoma is a hardwired identity, whereas the mesenchymal glioblastoma is an adaptive and metastable state downstream pro-inflammatory and differentiation cues, similarly wired in breast and lung tumors. Importantly, we discovered that innate immune cells divert glioblastoma cells into a proneural-to-mesenchymal transition causal to therapeutic resistance. Systematic phenotypic mapping using synthetic locus control regions (sLCRs) is a simple, automated, and scalable strategy for genetic tracing, generally applicable to study developmental and disease homeostasis. In glioblastoma, it uncovered causality between various (micro)environmental, genetic and pharmacological perturbations and mesenchymal commitment. Citation Format: Matthias Jurgen Schmitt, Carlos Company, Yuliia Dramaretska, Iros Barozzi, Andreas Gohrig, Sonia Kertalli, Melanie Grosmann, Heike Naumann, Jikke Wierikx, Danielle Hulsman, Rainer Glass, Massimo Squatrito, Michela Serresi, Gaetano Gargiulo. Phenotypic mapping of pathological crosstalk between glioblastoma and innate immune cells by synthetic genetic tracing [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-104.