scholarly journals Patient-derived Glioblastoma Stem cells transfer mitochondria through Tunneling Nanotubes in Tumor Organoids

2020 ◽  
Author(s):  
Giulia Pinto ◽  
Inés Saenz de Santa Maria ◽  
Patricia Chastagner ◽  
Emeline Perthame ◽  
Caroline Delmas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intercellular Communication ◽  
Brain Cancer ◽  
Therapy Resistance ◽  
Malignant Phenotype ◽  
Tunneling Nanotubes ◽  
Mitochondria Transfer ◽  
First Time ◽  
Tumor Organoids

Glioblastoma (GBM) is the most aggressive brain cancer and its relapse after surgery, chemo and radiotherapy appears to be led by GBM stem cells (GSLCs). Also, tumor networking and intercellular communication play a major role in driving GBM therapy-resistance. Tunneling Nanotubes (TNTs), thin membranous open-ended channels connecting distant cells, have been observed in several types of cancer, where they emerge to drive a more malignant phenotype. Here, we investigated whether GBM cells are capable to intercommunicate by TNTs. Two GBM stem-like cells (GSLCs) were obtained from the external and infiltrative zone of one GBM from one patient. We show, for the first time, that both GSLCs, grown in classical 2D culture and in 3D-tumor organoids, formed functional TNTs which allowed mitochondria transfer. In the organoid model, recapitulative of several tumor’s features, we observed the formation of a network between cells constituted of both Tumor Microtubes (TMs), previously observed in vivo, and TNTs. In addition, the two GSLCs exhibited different responses to irradiation in terms of TNT induction and mitochondria transfer, although the correlation with the disease progression and therapy-resistance needs to be further addressed. Thus, TNT-based communication is active in different GSLCs derived from the external tumoral areas associated to GBM relapse, and we propose that they participate together with TMs in tumor networking.

scholarly journals Patient-derived Glioblastoma Stem cells transfer mitochondria through Tunneling Nanotubes in Tumor Organoids

2020 ◽  
Author(s):  
Giulia Pinto ◽  
Inés Saenz-de-Santa-Maria ◽  
Patricia Chastagner ◽  
Emeline Perthame ◽  
Caroline Delmas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intercellular Communication ◽  
Brain Cancer ◽  
Therapy Resistance ◽  
Malignant Phenotype ◽  
Tunneling Nanotubes ◽  
Mitochondria Transfer ◽  
First Time ◽  
Tumor Organoids

AbstractGlioblastoma (GBM) is the most aggressive brain cancer and its relapse after surgery, chemo and radiotherapy appears to be led by GBM stem cells (GSLCs). Also, tumor networking and intercellular communication play a major role in driving GBM therapy-resistance. Tunneling Nanotubes (TNTs), thin membranous open-ended channels connecting distant cells, have been observed in several types of cancer, where they emerge to drive a more malignant phenotype. Here, we investigated whether GBM cells are capable to intercommunicate by TNTs. Two GBM stem-like cells (GSLCs) were obtained from the external and infiltrative zone of one GBM from one patient. We show, for the first time, that both GSLCs, grown in classical 2D culture and in 3D-tumor organoids, formed functional TNTs which allowed mitochondria transfer. In the organoid model, recapitulative of several tumor’s features, we observed the formation of a network between cells constituted of both Tumor Microtubes (TMs), previously observed in vivo, and TNTs. In addition, the two GSLCs exhibited different responses to irradiation in terms of TNT induction and mitochondria transfer, although the correlation with the disease progression and therapy-resistance needs to be further addressed. Thus, TNT-based communication is active in different GSLCs derived from the external tumoral areas associated to GBM relapse, and we propose that they participate together with TMs in tumor networking.

scholarly journals Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells

2021 ◽  
Vol 7 (5) ◽  
pp. eabe3445
Author(s):  
Yicun Wang ◽  
Jinhui Wu ◽  
Hui Chen ◽  
Yang Yang ◽  
Chengwu Xiao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Negative Feedback ◽  
Direct Interaction ◽  
Therapy Resistance ◽  
Negative Regulator ◽  
Chemotherapy Response ◽  
Genome Wide

Cancer stem cells (CSCs) are involved in tumorigenesis, recurrence, and therapy resistance. To identify critical regulators of sarcoma CSCs, we performed a reporter-based genome-wide CRISPR-Cas9 screen and uncovered Kruppel-like factor 11 (KLF11) as top candidate. In vitro and in vivo functional annotation defined a negative role of KLF11 in CSCs. Mechanistically, KLF11 and YAP/TEAD bound to adjacent DNA sites along with direct interaction. KLF11 recruited SIN3A/HDAC to suppress the transcriptional output of YAP/TEAD, which, in turn, promoted KLF11 transcription, forming a negative feedback loop. However, in CSCs, this negative feedback was lost because of epigenetic silence of KLF11, causing sustained YAP activation. Low KLF11 was associated with poor prognosis and chemotherapy response in patients with sarcoma. Pharmacological activation of KLF11 by thiazolidinedione effectively restored chemotherapy response. Collectively, our study identifies KLF11 as a negative regulator in sarcoma CSCs and potential therapeutic target.

scholarly journals Pathogenic Stress Induces Human Monocyte to Express an Extracellular Web of Tunneling Nanotubes

2021 ◽  
Vol 12 ◽  
Author(s):  
Michal Shahar ◽  
Auryan Szalat ◽  
Haim Rosen
Keyword(s):  
Intercellular Communication ◽  
Environmental Changes ◽  
Imaging System ◽  
Human Monocyte ◽  
Cell Types ◽  
Similar Response ◽  
Human Monocytes ◽  
Tunneling Nanotubes ◽  
Membrane Components

Actin-based tunneling nanotubes are a means of intercellular communication between remote cells. In the last decade, this type of nanotube was described in a wide variety of cell types and it became widely accepted that communication through these nanotubes is related to response to environmental changes. Few reports, however, are available regarding the expression of similar nanotubes in vivo or in primary cells. Moreover, the functional significance of this intercellular communication for health and disease is largely unknown. In this context, and as a first step in unraveling these questions, we examined the formation of similar nanotubes in primary peripheral human monocytes. To that end, we combined the use of a live cell imaging system along with advanced methods of fluorescent and scanning electron microscopy. This experimental approach reveals for the first time that the bacterial lipopolysaccharide endotoxin induces a transient expression of an unexpected abundance of actin-based tunneling nanotubes associated with vesicles. In addition, it was found that a similar response can be achieved by treating human monocytes with various bacterial and yeast membrane components, as well as with a viral component analog. In all these cases, this response is mediated by distinct complexes of toll-like receptors. Therefore, we suggest that the observed phenomena are related to a broad type of monocyte pathogen response, and raise the possibility that the phenomena described above may be involved in many clinical situations related to inflammation as a new topic of study.

scholarly journals Human Amniotic Fluid Cells Form Functional Gap Junctions with Cortical Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Anna Jezierski ◽  
Kerry Rennie ◽  
Roger Tremblay ◽  
Bogdan Zurakowski ◽  
Andreé Gruslin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Amniotic Fluid ◽  
Gap Junctions ◽  
Intercellular Communication ◽  
Cortical Cells ◽  
Alternative Source ◽  
Cx43 Expression ◽  
Injured Brain ◽  
Functional Brain Networks ◽  
First Time

The usage of stem cells is a promising strategy for the repair of damaged tissue in the injured brain. Recently, amniotic fluid (AF) cells have received a lot of attention as an alternative source of stem cells for cell-based therapies. However, the success of this approach relies significantly on proper interactions between graft and host tissue. In particular, the reestablishment of functional brain networks requires formation of gap junctions, as a key step to provide sufficient intercellular communication. In this study, we show that AF cells express high levels of CX43 (GJA1) and are able to establish functional gap junctions with cortical cultures. Furthermore, we report an induction of Cx43 expression in astrocytes following injury to the mouse motor cortex and demonstrate for the first time CX43 expression at the interface between implanted AF cells and host brain cells. These findings suggest that CX43-mediated intercellular communication between AF cells and cortical astrocytes may contribute to the reconstruction of damaged tissue by mediating modulatory, homeostatic, and protective factors in the injured brain and hence warrants further investigation.

scholarly journals Rapid Magneto-Sonoporation of Adipose-Derived Cells

Materials ◽  
2021 ◽  
Vol 14 (17) ◽  
pp. 4877
Author(s):  
Miriam Filippi ◽  
Boris Dasen ◽  
Arnaud Scherberich
Keyword(s):  
Stem Cells ◽  
Tissue Repair ◽  
Morphological Changes ◽  
Adipose Derived Stem Cells ◽  
Resonance Imaging ◽  
Membrane Resealing ◽  
First Time ◽  
Stimulation Of

By permeabilizing the cell membrane with ultrasound and facilitating the uptake of iron oxide nanoparticles, the magneto-sonoporation (MSP) technique can be used to instantaneously label transplantable cells (like stem cells) to be visualized via magnetic resonance imaging in vivo. However, the effects of MSP on cells are still largely unexplored. Here, we applied MSP to the widely applicable adipose-derived stem cells (ASCs) for the first time and investigated its effects on the biology of those cells. Upon optimization, MSP allowed us to achieve a consistent nanoparticle uptake (in the range of 10 pg/cell) and a complete membrane resealing in few minutes. Surprisingly, this treatment altered the metabolic activity of cells and induced their differentiation towards an osteoblastic profile, as demonstrated by an increased expression of osteogenic genes and morphological changes. Histological evidence of osteogenic tissue development was collected also in 3D hydrogel constructs. These results point to a novel role of MSP in remote biophysical stimulation of cells with focus application in bone tissue repair.

scholarly journals Ocoxin Modulates Cancer Stem Cells and M2 Macrophage Polarization in Glioblastoma

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Esther Hernández-SanMiguel ◽  
Ricardo Gargini ◽  
Teresa Cejalvo ◽  
Berta Segura-Collar ◽  
Paula Núñez-Hervada ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Macrophage Polarization ◽  
Antioxidant Properties ◽  
Therapy Resistance ◽  
Oral Solution ◽  
M2 Macrophage ◽  
Antioxidant Agents

Glioblastoma (GBM) is the most common and devastating primary brain tumor. The presence of cancer stem cells (CSCs) has been linked to their therapy resistance. Molecular and cellular components of the tumor microenvironment also play a fundamental role in the aggressiveness of these tumors. In particular, high levels of hypoxia and reactive oxygen species participate in several aspects of GBM biology. Moreover, GBM contains a large number of macrophages, which normally behave as immunosuppressive tumor-supportive cells. In fact, the presence of both, hypoxia and M2-like macrophages, correlates with malignancy and poor prognosis in gliomas. Antioxidant agents, as nutritional supplements, might have antitumor activity. Ocoxin® oral solution (OOS), in particular, has anti-inflammatory and antioxidant properties, as well as antitumor properties in several neoplasia, without known side effects. Here, we describe how OOS affects stem cell properties in certain GBMs, slowing down their tumor growth. In parallel, OOS has a direct effect on macrophage polarization in vitro and in vivo, inhibiting the protumoral features of M2 macrophages. Therefore, OOS could be a feasible candidate to be used in combination therapies during GBM treatment because it can target the highly resilient CSCs as well as their supportive immune microenvironment, without adding toxicity to conventional treatments.

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma

Gut ◽  
2021 ◽  
pp. gutjnl-2020-321175
Author(s):  
Shumei Song ◽  
Qiongrong Chen ◽  
Yuan Li ◽  
Guang Lei ◽  
Ailing Scott ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Antitumour Activity ◽  
Clinical Specimen ◽  
Therapy Resistance ◽  
In Vivo Studies ◽  
Induced Apoptosis

ObjectiveGastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.MethodsExtensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.ResultsOverexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.ConclusionsOur preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

In Vivo Fate Tracing Studies Using the SCL Stem Cell Enhancer: Embryonic Hematopoietic Stem Cells Significantly Contribute to Adult Hematopoiesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 559-559
Author(s):  
Joachim R. Gothert ◽  
Sonja E. Gustin ◽  
Mark A. Hall ◽  
Anthony R. Green ◽  
Berthold Gottgens ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
De Novo ◽  
Genetic Manipulation ◽  
Fetal Liver ◽  
Hematopoietic Stem ◽  
Reporter Mice ◽  
First Time

Abstract Evidence for the direct lineage relationship between embryonic and adult hematopoietic stem cells (HSCs) in the mouse is primarily indirect. In order to study this relationship in a direct manner we expressed the tamoxifen-inducible Cre-ERT-recombinase under the control of the SCL-stem-cell-enhancer in transgenic mice (HSC-SCL-Cre-ERT). To determine functionality, HSC-SCL-Cre-ERT transgenics were bred with the Cre-reporter-mice ROSA26R and R26R-EYFP. Flow-cytometric and transplantation studies revealed tamoxifen-dependent recombination occurring in more than 90% of adult long-term HSCs, whereas the targeted proportion within mature progenitor populations was significantly lower. Moreover, the transgene was able to irreversibly tag embryonic HSCs on days 10 and 11 of gestation. These cells contributed to bone marrow hematopoiesis five months later. In order to investigate whether the de novo HSC-generation is completed during embryogenesis, HSC-SCL-Cre-ERT marked fetal liver cells were transplanted into adult recipients. Strikingly, the proportion of marked cells within the transplanted and the in vivo-remaining HSC-compartment was not different, implying that no further HSC-generation occurred during late fetal and neonatal stages of development. These data demonstrate for the first time the direct lineage relationship between mid-gestation embryonic and adult HSCs in the mouse. Additionally, the HSC-SCL-Cre-ERT mice will provide a valuable tool to achieve temporally controlled genetic manipulation of HSCs.

scholarly journals Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts

2021 ◽  
Vol 22 (21) ◽  
pp. 11633
Author(s):  
Masashi Okada ◽  
Shuhei Suzuki ◽  
Keita Togashi ◽  
Asuka Sugai ◽  
Masahiro Yamamoto ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
High Sensitivity ◽  
Therapy Resistance ◽  
Folate Metabolism ◽  
Glioma Stem Cells ◽  
Tumor Initiating Cells ◽  
Dismal Prognosis

Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.

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