Immunotherapies have been transformative in other cancers, but brain cancers like glioblastoma have been stubbornly resistant. One of the biggest challenges in treating glioblastoma is how heterogeneous it is in every dimension. Even across a small tumor it varies dramatically in cell landscape, gene expression, protein composition, even in the mechanical structure of the tissue. Finding ways to overcome this challenge requires investigating brain cancers as complete interwoven systems. We focus on integrating spatial transcriptomics, proteomics, and extracellular matrix mapping to inform AI modeling approaches of identifying therapeutic targets that can reprogram the microenvironment to improve immunotherapy treatment. Our spatial multi-omics approach previously showed how immunotherapy treatments in glioma models created fibrotic scars in the brain, and that these scars could block immune cells, and serve as safe as havens for tumor cells to survive treatment. We're now aiming to applying these approaches to better understand the tumor immune microenvironment in the full context of their extracellular environment.

Fibrosis and extracellular matrix create environments that can strongly influence tumor survival and immune response. The challenge is that ECM biology is easy to characterize in vivo, but extemely difficult to perturb and manipulate in live models. ECM niches vary across a tumor, change with therapy, and couple biochemical signaling with tissue mechanics, all of which can reshape cell migration, dormancy, and immune activity. We aim to address this challenge with experimental systems that recreate the extracellular environments observed in patient tumors. Patient-derived organoid and assembloid platforms and bioengineered matrix structures allow direct interrogation of how ECM-linked signaling and mechanical cues influence immune cell trafficking, immune suppression, and tumor cell dormancy following treatment. We're reseraching novel strategies to therapeutically modulate and target extracellular environments to eliminate minimal residual disease after front line therapy, to reprogram the ECM environment to synergize with exisiting treatments, and to target precision guided immunotherapies against therapy resistant cancer cells.