Despite advances in cancer molecular profiling, successful therapeutic development has been hindered by challenges in identifying tumor-specific mechanisms that can be targeted without consequence to healthy tissue. Discrimination between tumor and host cells that comprise the tumor microenvironment remains a difficult yet important task for defining tumor cell signatures. Correspondingly, a computational framework capable of accurately distinguishing tumor from non-tumor cells has yet to be developed. Cell annotation algorithms are largely unable to assign integrated genomic and transcriptional profiles to single cells on a cell-by-cell basis. To address this, we developed the Single Cell Rule Association Mining (SCRAM) tool that integrates RNA-inferred genomic alterations with co-occurring cell type transcriptional signatures for individual cells. Applying our pipeline to human and mouse glioma, we identified tumor cell trajectories that recapitulate temporally-restricted developmental paradigms and feature unique co-occurring genomic and transcriptomic identities. Specifically, we describe and validate two previously unreported tumor cell populations with immune and neuronal signatures as hallmarks of human glioma subtypes. In vivo modeling revealed an immune-like tumor cell population can direct CD8+ T cell responses and survival outcomes. In parallel, electrophysiology and Patch-seq studies in human tumors confirmed a frequent subset of neuronal-like glioma cells that fire action potentials but retain the morphology of glia. These collective studies report the existence of new glioma cell types with functional properties akin to their non-tumor analogs and demonstrate the ability of SCRAM to identify and characterize these cell types in unprecedented detail.
The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.
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