Intra-tumor heterogeneity (ITH), the diversity of cells within a tumor, has been recognized for decades as a fundamental property of cancer and as a major barrier for successful therapies. However, our understanding of ITH and our ability to eradicate heterogeneous tumors remain poor. One of the cancer types in which such heterogeneity is well known and thought to be highly important is glioblastoma (GBM) and other types of glioma such as IDH-mutant glioma. Over the last decade, single cell RNA sequencing (scRNA-seq) and other technologies enabled significant advances in defining ITH, opening up new avenues in cancer research. We previously applied scRNA-seq to GBM and other gliomas and found that similar cellular states (as defined by large-scale expression programs) are observed across patients. Two GBMs would typically differ from one another by the expression levels of hundreds of genes, yet beyond those differences they share an internal pattern of ITH: each GBM is likely to contain multiple malignant subpopulations reflecting four stereotypic cellular states, one with upregulation of astrocyte (AC) genes, another expressing mesenchymal markers (e.g. VIM, FN1), and two additional subpopulations with increased expression of genes of neural progenitor cells (NPC) and oligodendrocyte progenitor cells (OPC). Each of these states were found in many glioblastomas, but with variable cellular frequencies, and with the potential to proliferate and interconvert. Together, these “core” cellular states define a central aspect of GBM biology that may dictate many phenotypes and clinical features. Thus, it is now crucial to better understand how these states are regulated, and most notably how they relate to invasion and drug resistance.
Apart from these common and previously defined states, we speculate that additional states of functional and clinical significance might also exist and have yet to be fully described and appreciated. For example, previous studies examined the tumor samples that were surgically removed, but were unable to evaluate cells that diffuse from the tumor and invade the brain parenchyma. Such cells are of immense clinical significance as they cannot be surgically removed and ultimately lead to recurrence. Whether such invasive cells differ from the cells in the core of the tumor remains unknown, and if so, it would motivate new therapeutic strategies to specifically eliminate the invading cells. Thus, in addition to the core cellular states, we propose to identify and study rare and invasive cellular states.
