Abstract
High-grade glioma is one of the most lethal human cancers characterized by extensive tumor heterogeneity. In order to identify cellular and molecular mechanisms that drive tumor heterogeneity of this lethal disease, we performed single-cell RNA sequencing analysis of one high-grade glioma. Accordingly, we analyzed the individual cellular components in the ecosystem of this tumor. We found that tumor-associated macrophages are predominant in the immune microenvironment. Furthermore, we identified five distinct subpopulations of tumor cells, including one cycling, two OPC/NPC-like and two MES-like cell subpopulations. Moreover, we revealed the evolutionary transition from the cycling to OPC/NPC-like and MES-like cells by trajectory analysis. Importantly, we found that SPP1/CD44 interaction plays a critical role in macrophage-mediated activation of MES-like cells by exploring the cell-cell communication among all cellular components in the tumor ecosystem. Finally, we showed that high expression levels of both SPP1 and CD44 correlate with an increased infiltration of macrophages and poor prognosis of glioma patients. Taken together, this study provided a single-cell atlas of one high-grade glioma and revealed a critical role of macrophage-mediated SPP1/CD44 signaling in glioma progression, indicating that the SPP1/CD44 axis is a potential target for glioma treatment.
Highlights
Glioma is the most common type of primary brain cancers (Louis et al, 2016)
We provided a single-cell atlas of the cellular components in this tumor, and revealed essential roles of tumor-immune cell interactions in promoting glioma progression, such as the crosstalk between macrophages and tumor cells mediated by SPP1/CD44 interaction
isocitrate dehydrogenase (IDH) wild-type glioma has been observed with aggressive phenotypes and poor prognosis compared to the IDH mutant glioma (Agnihotri et al, 2014; Picca et al, 2018)
Summary
Glioma is the most common type of primary brain cancers (Louis et al, 2016). According to the WHO classification, glioma has been defined as pilocytic astrocytoma (grade I), low-grade astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GBM, grade IV). Glioma with wild-type IDH genes often shows aggressive behavior and poor prognosis (Omuro and DeAngelis, 2013; Picca et al, 2018). High-grade glioma has been shown to exhibit extensive intra-tumoral heterogeneity, which leads to increased resistance to therapy and tumor progression (Bedard et al, 2013; Darmanis et al, 2017). It has been shown that crosstalk between cellular components in the tumor ecosystem plays important roles in tumor progression. Exploring the diversity and heterogeneity of cellular compositions in the tumor ecosystem helps to understand the mechanisms underlying tumor progression, and provides new directions to develop targeted therapies. The intra-tumoral heterogeneity of cellular components and their crosstalk are largely unknown in highgrade glioma. There is an urgent need to further dissect the intra-tumoral heterogeneity of glioma
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