Glioblastoma Stem Cells: Driving Resilience through Chaos

Prager, Briana C.; Bhargava, Shruti; Mahadev, Vaidehi; Hubert, Christopher G.; Rich, Jeremy

doi:10.1016/j.trecan.2020.01.009

“…The tissues were then desegregated and cultured in stem cell medium [7] to enrich in GBM stem cells rather than differentiated ones [33], and grown in suspension in neurosphere-like aggregates (Fig.1B). To further characterize the two populations, named C1 and C2, we monitored the expression of genes associated with different cell types, from differentiated to progenitor/stem cells [4,6,[41][42][43][44]. GFAP and CHI3L1 (respectively astrocytic and mesenchymal markers) were not expressed and low expression was observed for the neural markers Tubβ3 and GAP43.…”

Section: ) Patient-derived Gbm Cells With Stem-like Features Form Tnmentioning

confidence: 99%

“…Although these treatments have been proven to be effective in extending patients survival [2], lethal relapse from these peripheral regions occurs in 100% the cases. The elevated intra-tumoral heterogeneity seems to be at the origin of the relapse and particularly due to the presence of GBM stem cells (GSCs) that have been found to be the most resistant to treatments [3][4][5][6]. Moreover, it has been shown that post-surgical treatments can induce cellular plasticity and trans-differentiation resulting in more aggressive phenotypes [7].…”

Section: Introductionmentioning

confidence: 99%

Patient-derived glioblastoma stem cells transfer mitochondria through tunneling nanotubes in tumor organoids

Pinto

¹

,

Saenz-de-Santa-Maria

²

,

Chastagner

³

et al. 2021

Biochemical Journal

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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.

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“…To enhance the therapeutic e cacy of MK-8931, we found that a low dose of irradiation (IR) remarkably augmented TAM in ltration and effectively synergized with MK-8931. Radiotherapy is a standard treatment for GBM 17 , but this tumor is highly resistant to IR, partially due to the population of GSCs that resist to conventional treatments and contribute to tumor recurrence 22,23 . In addition, IR often triggers an in ammation response and remodulate the tumor microenvironment to induce therapeutic resistance 67,68 .…”

Section: Discussionmentioning

confidence: 99%

“…GBM inevitably recurs after surgical resection and radio-chemotherapy 20,21 . We and the others have demonstrated that pTAMs, glioma stem cells (GSCs), and the interplay between them play vital roles in promoting tumor progression and therapeutic resistance in GBMs 7,22,23 . TAMs and GSCs are often located in the perivascular niche in GBM 10,24 and actively interact at cellular and molecular levels to support malignant growth [10][11][12]25 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of BACE1 Facilitates Macrophage-based Immunotherapy to Suppress Malignant Growth of Glioblastoma

Zhai¹,

Huang²,

Wen³

et al. 2020

Preprint

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Malignant tumors, including glioblastoma (GBM), contain abundant tumor-associated macrophages (TAMs) that mainly promote tumor growth and therapeutic resistance. Reprograming tumor-promoting TAMs (pTAMs) into tumor-suppressive TAMs (sTAMs) represents an attractive therapeutic strategy. We discovered that inhibition of the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) by MK-8931 potently redirects pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells to suppress the malignant growth of GBM. Moreover, low doses of radiation markedly enhance TAM infiltration and synergize with MK-8931 treatment. BACE1 is preferentially expressed by pTAMs in human GBMs and is required for maintaining pTAM polarization through trans-IL-6/sIL-6R/STAT3 signaling. As several BACE1 inhibitors, including MK-8931, previously developed for Alzheimer's disease, were shown in clinical trials to be safe for humans, repurposing these inhibitors for cancer therapy should be straightforward. Collectively, this study offers a promising therapeutic approach, through inhibition of BACE1, to facilitate the macrophage-based tumor immunotherapy.

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“…Authors' information: Giulia Pinto 1,2 (giulia.pinto@pasteur.fr), Inés Saenz-de-Santa-Maria 1 (ines.saenz-de-santa-maria@pasteur.fr); Patricia Chastagner 1 (patricia.chastagner@pasteur.fr), Emeline Perthame 3 (emeline.perthame@pasteur.fr), Caroline Delmas 4 (Delmas.Caroline@iuctoncopole.fr), Christine Toulas 4 (Toulas.Christine@iuct-oncopole.fr), Elizabeth Moyal-Jonathan-Cohen 4 (Moyal.Elizabeth@iuct-oncopole.fr), Christel Brou 1 (christel.brou@pasteur.fr), Chiara Zurzolo 1 (chiara.zurzolo@pasteur.fr). Scale bar: 5 μm.…”

Section: Declarationsunclassified

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

Pinto

¹

,

Saenz-de-Santa-Maria

²

,

Chastagner

³

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Glioblastoma Stem Cells: Driving Resilience through Chaos

Cited by 238 publications

References 116 publications

Patient-derived glioblastoma stem cells transfer mitochondria through tunneling nanotubes in tumor organoids

Patient-derived glioblastoma stem cells transfer mitochondria through tunneling nanotubes in tumor organoids

Inhibition of BACE1 Facilitates Macrophage-based Immunotherapy to Suppress Malignant Growth of Glioblastoma

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

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