Quiescent human glioblastoma cancer stem cells drive tumor initiation, expansion, and recurrence following chemotherapy

Xie, Xiao‐Bi; Laks, Dan R.; Sun, Duxin; Ganbold, Mungunsarnai; Wang, Zilai; Pedraza, Alicia; Bale, Tejus; Tabar, Viviane; Brennan, Cameron; Zhou, Xiuping; Parada, Luis F.

doi:10.1016/j.devcel.2021.12.007

Cited by 92 publications

(90 citation statements)

References 58 publications

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“…The observation of an amplified antitumoral response in clinically relevant 3D models emphasizes the potential of this approach. A very recent publication described quiescent GBM cancer stem cells that become activated upon chemotherapy [ 58 ]. Subsequent studies on organoid cultures will show whether our combined CDKi/SpyADI has the capacity to catch these “quiescent” GBM stem cells by counteracting their potential to evade anti-proliferative therapies.…”

Section: Discussionmentioning

confidence: 99%

Implementation of a combined CDK inhibition and arginine-deprivation approach to target arginine-auxotrophic glioblastoma multiforme cells

et al. 2022

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Constitutive activation of cyclin-dependent kinases (CDKs) or arginine auxotrophy are hallmarks of Glioblastoma multiforme (GBM). The latter metabolic defect renders tumor cells vulnerable to arginine-depleting substances, such as arginine deiminase from Streptococcus pyogenes (SpyADI). Previously, we confirmed the susceptibility of patient-derived GBM cells towards SpyADI as well as CDK inhibitors (CDKis). To improve therapeutic effects, we here applied a combined approach based on SpyADI and CDKis (dinaciclib, abemaciclib). Three arginine-auxotrophic patient-derived GBM lines with different molecular characteristics were cultured in 2D and 3D and effects of this combined SpyADI/CDKi approach were analyzed in-depth. All CDKi/SpyADI combinations yielded synergistic antitumoral effects, especially when given sequentially (SEQ), i.e., CDKi in first-line and most pronounced in the 3D models. SEQ application demonstrated impaired cell proliferation, invasiveness, and viability. Mitochondrial impairment was demonstrated by increasing mitochondrial membrane potential and decreasing oxygen consumption rate and extracellular acidification rate after SpyADI/abemaciclib monotherapy or its combination regimens. The combined treatment even induced autophagy in target cells (abemaciclib/SpyADI > dinaciclib/SpyADI). By contrast, the unfolded protein response and p53/p21 induced senescence played a minor role. Transmission electron microscopy confirmed damaged mitochondria and endoplasmic reticulum together with increased vacuolization under CDKi mono- and combination therapy. SEQ-abemaciclib/SpyADI treatment suppressed the DSB repair system via NHEJ and HR, whereas SEQ-dinaciclib/SpyADI treatment increased γ-H2AX accumulation and induced Rad51/Ku80. The latter combination also activated the stress sensor GADD45 and β-catenin antagonist AXIN2 and induced expression changes of genes involved in cellular/cytoskeletal integrity. This study highlights the strong antitumoral potential of a combined arginine deprivation and CDK inhibition approach via complex effects on mitochondrial dysfunction, invasiveness as well as DNA-damage response. This provides a good starting point for further in vitro and in vivo proof-of-concept studies to move forward with this strategy.

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Section: Discussionmentioning

confidence: 99%

Implementation of a combined CDK inhibition and arginine-deprivation approach to target arginine-auxotrophic glioblastoma multiforme cells

et al. 2022

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“…Here, we implemented label tracing functional genomic techniques to human patient AML specimens. This unbiased approach enables molecular and functional analyses of diverse leukemia initiating and quiescent LRC stem cells that evade detection by currently known cell surface markers, as also proposed by others 19,20,46 .…”

Section: Discussionmentioning

confidence: 88%

Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance

Takao

Morell

Brown

et al. 2022

Preprint

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Many human cancers, including acute myeloid leukemia (AML), arise from mutations of stem and progenitor cells. Immunophenotypic profiling has shown that leukemia develops hierarchically, with mutations in leukemia stem cells associated with disease propagation and relapse1,2. Although leukemia initiating cells can be enriched using cell surface markers, their frequency tends to be variable and low, obscuring mechanisms and hindering effective therapies3,4. To define AML stem cells in human patients, we performed functional genomic profiling of diverse leukemias using label tracing techniques designed to preserve hematopoietic stem cell (HSC) function in vivo. We found that propagation of human AML is mediated by a rare but distinct quiescent label-retaining cell (LRC) population that evades detection by currently known immunophenotypic markers. We show that human AML LRC quiescence is reversible, sparing genetic clonal competition that maintains its epigenetic inheritance. LRC quiescence is defined by distinct promoter-centered chromatin and gene expression dynamics, and controlled by a novel AP-1/ETS transcription factor network, which is associated with disease persistence and chemotherapy resistance in diverse patients. These results enable prospective isolation and functional genetic manipulation of immunophenotypically-varied leukemia stem cells in human patient specimens, as well as establish the key functions of epigenetic plasticity in leukemia development and therapy resistance. We anticipate that these findings will lead to the elucidation of essential properties of leukemia stem cell quiescence and the design of therapeutic strategies for their clinical identification and control.

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“…The glioblastoma stem cells (GSCs) present in GBM widely contribute to GBM recurrence following surgery and to resistance to both radio- and chemotherapies [ 144 , 147 , 148 ]. These GSCs undergo highly dynamic changes of their genetic, epigenetic, and metabolic features, which supports their escape from GBM therapies [ 149 ].…”

Section: Brain Tumorsmentioning

confidence: 99%

Intercellular Communication in the Brain through Tunneling Nanotubes

Khattar

Safi

Rodriguez

et al. 2022

Cancers

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Intercellular communication is essential for tissue homeostasis and function. Understanding how cells interact with each other is paramount, as crosstalk between cells is often dysregulated in diseases and can contribute to their progression. Cells communicate with each other through several modalities, including paracrine secretion and specialized structures ensuring physical contact between them. Among these intercellular specialized structures, tunneling nanotubes (TNTs) are now recognized as a means of cell-to-cell communication through the exchange of cellular cargo, controlled by a variety of biological triggers, as described here. Intercellular communication is fundamental to brain function. It allows the dialogue between the many cells, including neurons, astrocytes, oligodendrocytes, glial cells, microglia, necessary for the proper development and function of the brain. We highlight here the role of TNTs in connecting these cells, for the physiological functioning of the brain and in pathologies such as stroke, neurodegenerative diseases, and gliomas. Understanding these processes could pave the way for future therapies.

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Quiescent human glioblastoma cancer stem cells drive tumor initiation, expansion, and recurrence following chemotherapy

Cited by 92 publications

References 58 publications

Implementation of a combined CDK inhibition and arginine-deprivation approach to target arginine-auxotrophic glioblastoma multiforme cells

Implementation of a combined CDK inhibition and arginine-deprivation approach to target arginine-auxotrophic glioblastoma multiforme cells

Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance

Intercellular Communication in the Brain through Tunneling Nanotubes

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