Does the spatial organization of tumor and immune cells reveal potentially targetable tumor-immune interactions?

Glioblastoma (GBM), a type of brain cancer, is a devastating disease with a median survival of 15 months and 5-year survival rate of 10%. Immunotherapies and other novel treatments have been ineffective against GBM; one reason may be the multi-level heterogeneity that typifies this disease. Each GBM tumor is heterogeneous with respect to genetics, tumor cell state, immune microenvironment, and larger spatial domains that can be identified by radiology and pathology. Genomic sequencing and single cell RNA sequencing reveal heterogeneity in both intra-tumoral genetics and gene expression, which may contribute to tumor evolvability and drug resistance. Adding to this complexity, “heterotypic” interactions between tumor cells and immune cells are believed to shape the tumor ecosystem and the clinical trajectory of GBM and other cancers in ways that are only beginning to be understood.

The mechanisms through which transcriptional, genetic, and immunological heterogeneity collectively drive tumor evolution and drug response remain unknown. Dr. Petti’s project will address several key areas of GBM biology that have not been systematically explored. First, she plans to focus on the infiltrating tumor margin, the area that gives rise to most recurrent tumors. In contrast, most GBM studies have focused on the tumor core. Second, GBM has not been well-studied using techniques that preserve information about spatial organization and intercellular interactions. Thus, it is not known which tumor cells interact with each other and with the immune microenvironment. Dr. Petti plans to use spatial transcriptomics, a new technology that incorporates spatial information into high-resolution transcriptomic data, thereby enabling the study of intercellular interactions and spatial organization at nearly single-cell resolution. She will integrate spatial transcriptomic data with single nucleus RNA sequencing data and exome data in order to answer novel questions about the relationship of the tumor ecosystem to the tumor genome. Finally, Dr. Petti plans to utilize a unique experimental design – spatial transcriptomic time courses in mouse models of human tumors, known as patient-derived xenografts – to elucidate the step-wise changes that occur during tumorigenesis and treatment response. Through this work, Dr. Petti hopes to shed light on how tumor cells react to each other and the immune system to find new ways to treat glioblastoma and potentially other cancers.