Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression

Alvarado, Alvaro G.; Thiagarajan, P. S.; Mulkearns-Hubert, Erin E.; Silver, Daniel J.; Hale, James S.; Alban, Tyler J.; Turaga, Soumya M.; Jarrar, Awad; Reizes, Ofer; Longworth, Michelle S.; Vogelbaum, Michael A.; Lathia, Justin D.

doi:10.1016/j.stem.2016.12.001

Cited by 162 publications

(133 citation statements)

References 52 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, only cluster 3 may be avoiding immune destruction due to the deregulation of Toll-like receptor signaling pathway. Glioblastoma is known to have a strongly immunosuppressive microenvironment, thus blocking these cells by activating downstream TLR signaling pathways can reduce tumor growth and disrupt CSC self-renewal (73,74).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic models of signaling pathways deconvolute the functional landscape of glioblastoma at single cell resolution

Peña‐Chilet

Loucera

et al. 2019

Preprint

View full text Add to dashboard Cite

The rapid development of single cell RNA-sequencing (scRNA-seq) technologies is revealing an unexpectedly large degree of heterogeneity in gene expression levels across the different cells that compose the same tissue sample. However, little is known on the functional consequences of this heterogeneity and the contribution of individual cell-fate decisions to the collective behavior of the tissues these cells are part of. Mechanistic models of signaling pathways have already proven to be useful tools for understanding relevant aspects of cell functionality. Here we propose to use this mechanistic modeling strategy to deconvolute the complexity of the functional behavior of a tissue by dissecting it into the individual functional landscapes of its component cells by using a single-cell RNA-seq experiment of glioblastoma cells. This mechanistic modeling analysis revealed a high degree of heterogeneity at the scale of signaling circuits, suggesting the existence of a complex functional landscape at single cell level. Different clusters of neoplastic glioblastoma cells have been characterized according to their differences in signaling circuit activity profiles, which only partly overlap with the conventional glioblastoma subtype classification. The activity of signaling circuits that trigger cell functionalities which can easily be assimilated to cancer hallmarks reveals different functional strategies with different degrees of aggressiveness followed by any of the clusters.In addition, mechanistic modeling allows simulating the effect of interventions on the components of the signaling circuits, such as drug inhibitions. Thus, effects of drug inhibitions at single cell level can be dissected, revealing for the first time the mechanisms that individual cells use to avoid the effect of a targeted therapy which explain why and how a small proportion of cells display, in fact, different degrees of resistance to the treatment. The results presented here strongly suggest that mechanistic modeling at single cell level not only allows uncovering the molecular mechanisms of the tumor progression but also can predict the success of a treatment and can contribute to a better definition of therapeutic targets in the future.

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanistic models of signaling pathways deconvolute the functional landscape of glioblastoma at single cell resolution

Peña‐Chilet

Loucera

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…With the exception of two polyunsaturated ceramide species (HexCer 34:1;2 and HexCer 34:1;3), the lipids generated within the HFD-fed, tumor-bearing brain were saturated, mono-, or di-unsaturated lipid species, consistent with heavy consumption of a saturated fat-based diet. As ceramide lipids have a strong association with cellular stress (35,36), which is commonly induced within the caustic growth zones (37,38) of GBM, we omitted these species from our analysis. Based on this non-targeted lipid assessment, we concluded that HFD consumption induced accumulation of saturated fats within the brain and tumor microenvironment of HFD-fed animals.…”

Section: Hfd Consumption Drives Stem Cell Phenotype Enrichmentmentioning

confidence: 99%

Cancer Stem Cell Enrichment and Metabolic Substrate Adaptability are Driven by Hydrogen Sulfide Suppression in Glioblastoma

Silver

Roversi

Bithi

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Glioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.One Sentence SummaryConsumption of a high-fat diet (HFD) accelerates glioblastoma (GBM) by inhibiting the production and signaling of the tumor-suppressive metabolite hydrogen sulfide (H2S).

show abstract

“…In some experiments, previously established GBM xenografts obtained from Duke University and the University of Florida were used and maintained as previously described (44,45).…”

Section: Primary Human Glioblastoma Cellsmentioning

confidence: 99%

ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells

Hale

Jimenez-Pascual

Kordowski

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSCs), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs. This loop consists of an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. This signaling axis induces upregulation of Zinc finger E-box-binding homeobox 1 (ZEB1) that regulates ADAMDEC1 expression, creating a positive feedback loop. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. Statement of SignificanceCancer stem cells (CSC) drive tumor growth in many cancers including glioblastoma. We identified a novel sheddase, a disintegrin and metalloproteinase domain-like protein decysin 1, that initiates a fibroblast growth factor autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce glioblastoma growth.

show abstract

Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression

Cited by 162 publications

References 52 publications

Mechanistic models of signaling pathways deconvolute the functional landscape of glioblastoma at single cell resolution

Mechanistic models of signaling pathways deconvolute the functional landscape of glioblastoma at single cell resolution

Cancer Stem Cell Enrichment and Metabolic Substrate Adaptability are Driven by Hydrogen Sulfide Suppression in Glioblastoma

ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells

Contact Info

Product

Resources

About