Activation of NOTCH Signaling by Tenascin-C Promotes Growth of Human Brain Tumor-Initiating Cells

Sarkar, Susobhan; Mirzaei, Reza; Zemp, Franz J.; Wu, Wei; Senger, Donna L.; Robbins, Stephen M.; Yong, V. Wee

doi:10.1158/0008-5472.can-16-2171

Cited by 62 publications

(59 citation statements)

References 50 publications

(68 reference statements)

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“…BTICs were isolated from resected specimens of patients with glioblastoma (7,9,26,36). We used three BTIC lines derived from glioma patients designated BT012, BT025, and BT048.…”

Section: Culture Of Human Bticsmentioning

confidence: 99%

“…These lines had different genetic mutations (26) including BT012: EGFR wildtype (wt), p53 wt, PTEN mutant (mt, frameshift in codon 328); BT025: EGFR wt, p53 mt (T125R), PTEN mt (G129R); and BT048: EGFR mt (K294R, G598V), p53 wt, PTEN wt. BT025 and BT048 were employed in the majority of experiments since they were characterized extensively in our previous study (6)(7)(8)(9)26). To propagate the lines, BTICs were dissociated and plated into T25 flasks at regular intervals and grown in serum free culture medium supplemented with epidermal growth factor and fibroblast growth factor-2 in 5% CO 2 as described elsewhere (36,37); we refer to this as BTIC medium.…”

Section: Culture Of Human Bticsmentioning

confidence: 99%

“…For neurosphere assay, BTIC cells (10,000 cells/well/100µl of serum free BTIC medium) were plated into 96-well plates (7,26,36). The resultant number of spheres above the 60 µm diameter cutoff, a convenient parameter to describe growth characteristics, was monitored after 72 h by photographing multiple fields per well with subsequent image analyses.…”

Section: Evaluation Of Btic Growthmentioning

confidence: 99%

“…The most aggressive form, glioblastoma multiforme, has a dismal prognosis with a median survival of 15 months; <10% of patients survive beyond 5 years (1)(2)(3). The poor prognosis of malignant gliomas is attributed in part to the existence of glioma stem cells, also called brain tumorinitiating cells (BTICs) (4)(5)(6)(7)(8)(9). BTICs are resistant to therapies as they continue to seed and form new tumor foci in the brain.…”

Section: Introductionmentioning

confidence: 99%

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Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Sarkar

Mirzaei

et al. 2020

Front. Immunol.

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Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas.

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“…BTICs were isolated from resected specimens of patients with glioblastoma (7,9,26,36). We used three BTIC lines derived from glioma patients designated BT012, BT025, and BT048.…”

Section: Culture Of Human Bticsmentioning

confidence: 99%

Section: Culture Of Human Bticsmentioning

confidence: 99%

Section: Evaluation Of Btic Growthmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Sarkar

Mirzaei

et al. 2020

Front. Immunol.

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“…Previous observations have suggested a key role of the Notch-Jagged signaling axis in mediating CSC properties (14,(41)(42)(43). Therefore, we next focused on what signals in the TME can promote Notch-Jagged signaling.…”

Section: Inflammatory Cytokines Can Promote a Hybrid E/m Phenotype Bymentioning

confidence: 99%

Towards understanding cancer stem cell heterogeneity in the tumor microenvironment

Bocci

Gearhart-Serna

Boareto

et al. 2018

Preprint

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The Epithelial-Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) formation are two paramount processes driving tumor progression, therapy resistance and cancer metastasis. Some recent experiments show that cells with varying EMT and CSC phenotypes are spatially segregated in the primary tumor. The underlying mechanisms generating such spatiotemporal dynamics and heterogeneity in the tumor micro-environment, however, remain largely unexplored. Here, we show through a mechanism-based dynamical model that the diffusion of EMT-inducing signals such as TGF-β in a tumor tissue, together with non-cell autonomous control of EMT and CSC decisionmaking via juxtacrine signaling mediated via the Notch signaling pathway, can explain experimentally observed disparate localization of subsets of CSCs with varying EMT states in the tumor. Our simulations show that the more mesenchymal CSCs lie at the invasive edge, while the hybrid epithelial/mesenchymal (E/M) CSCs reside in the tumor interior. Further, motivated by the role of Notch-Jagged signaling in mediating EMT and stemness, we investigated the microenvironmental factors that promote Notch-Jagged signaling. We show that many inflammatory cytokines that can promote Notch-Jagged signaling such as IL-6 can (a) stabilize a hybrid E/M phenotype, (b) increase the likelihood of spatial proximity of hybrid E/M cells, and (c) expand the fraction of CSCs. To validate the predicted connection between Notch-Jagged signaling and stemness, we knocked down JAG1 in hybrid E/M SUM149 human breast cancer cells in vitro. JAG1 knockdown significantly restricted organoid formation, confirming the key role that Notch-Jagged signaling can play in tumor progression. Together, our integrated computational-experimental framework reveals the underlying principles of spatiotemporal dynamics of EMT and CSCs in the tumor microenvironment. Significance statementThe presence of heterogeneous subsets of cancer stem cells (CSCs) remains a clinical challenge. These subsets often occupy different regions in the primary tumor and have varied epithelialmesenchymal phenotypes. Here, we device a theoretical framework to investigate how the tumor microenvironment (TME) modulates this spatial patterning. We find that a spatial gradient of EMTinducing signal, coupled with juxtacrine Notch-JAG1 signaling triggered by inflammatory cytokines in TME, explains this spatial heterogeneity. Finally, in vitro JAG1 knockdown experiments in triple negative breast cancer cells severely restricts the growth of tumor organoid, hence validating the association between JAG1 and CSC fraction. Our results offer insights into principles of spatiotemporal patterning in TME, and identifies a relevant target to alleviate multiple CSC subsets -JAG1.

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Characterization of a FOXG1:TLE1 transcriptional network in glioblastoma‐initiating cells

et al. 2018

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Glioblastoma (GBM) is the most common and deadly malignant brain cancer of glial cell origin, with a median patient survival of less than 20 months. Transcription factors FOXG1 and TLE1 promote GBM propagation by supporting maintenance of brain tumour‐initiating cells (BTICs) with stem‐like properties. Here, we characterize FOXG1 and TLE1 target genes in GBM patient‐derived BTICs using ChIP‐Seq and RNA‐Seq approaches. These studies identify 150 direct FOXG1 targets, several of which are also TLE1 targets, involved in cell proliferation, differentiation, survival, chemotaxis and angiogenesis. Negative regulators of NOTCH signalling, including CHAC1, are among the transcriptional repression targets of FOXG1:TLE1 complexes, suggesting a crosstalk between FOXG1:TLE1 and NOTCH‐mediated pathways in GBM. These results provide previously unavailable insight into the transcriptional programs underlying the tumour‐promoting functions of FOXG1:TLE1 in GBM.

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Activation of NOTCH Signaling by Tenascin-C Promotes Growth of Human Brain Tumor-Initiating Cells

Cited by 62 publications

References 50 publications

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Towards understanding cancer stem cell heterogeneity in the tumor microenvironment

Characterization of a FOXG1:TLE1 transcriptional network in glioblastoma‐initiating cells

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