Tumor cell plasticity, heterogeneity and resistance in crucial microenvironmental niches in glioma

Abstract

<jats:title>Abstract</jats:title> <jats:p>Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches could be determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitated resistance against cytotoxic effects of radiotherapy and chemotherapy - independently of each other, but with additive effects. Perivascular glioblastoma cells were particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depended on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induced resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.</jats:p>

Analysis of U87 glioma cells by dielectrophoresis

“…Hence, the development of dielectrophoretic characterization methods in conjunction with current technologies will foster unrevealing cellular individuality and consequently heterogeneity of populations to fight diseases such as GBM [44][45][46][47][48][49]. GBM is a highly resistive and invasive type of brain tumor, arising with multiform structures that enormously enhance its heterogeneity [1][2][3][4][5][6][7][8]. A precise and accurate characterization of cells in the GBM microenvironment will lead better diagnosis, prognosis, and personalized treatment strategies [9][10][11][12][13].…”

“…Glioblastoma multiforme (GBM) is the most aggressive and invasive brain cancer of glial cells in humans [1][2][3]. It has massive intratumoral and intertumoral heterogeneity due to its highly complex and dynamic microenvironment.…”

Analysis of single-cell RNA-sequencing data to identify quiescent and proliferating neural cell populations in Glioblastoma

“…Thus the evidence so far indicates a non-hierarchical model where cells niches with strong cellular plasticity are at the core of recreating intratumoral heterogeneity. Evidence supporting intratumoral cell niches with high cellular plasticity in glioblastoma comes from a recent study by Jung, Erik, et al [14]. The authors show the existence two complementary cellular niches driving tumor progression and therapy resistance in GBM.…”

“…A number of recent studies have utilized scRNAseq to study gliomas of different origin and grade generating a wealth of data on the transcriptomic nature of cells within the tumor [14,17,19,22]. While these studies primarily focused on different states of gliomas and tumor-immune cell interaction, few studies have tried to delineate differences in cellular states within neural cells in GBM.…”

Integrated pan‐cancer of AURKA expression and drug sensitivity analysis reveals increased expression of AURKA is responsible for drug resistance

“…Scientists are faced with variety of cancer challenges; however, tumor heterogeneity, which has the potential to be seen in the expression level of genes, mutations, epigenetic, and microenvironment, has been on the top of attentions. 4 Therefore, what can help controlling, treating, and diagnosing cancers is identifying key genes or the vital pathways among all sorts of cancers. 5,6 AURKA is a serine/threonine kinase that is crucial in controlling of mitosis progression, centrosome maturation/separation, and mitotic spindle function.…”