Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression

Wang, Xiuxing; Prager, Briana C.; Wu, Qiulian; Kim, Leo J.Y.; Gimple, Ryan C.; Shi, Yu; Yang, Kailin; Morton, Andrew; Zhou, Wenchao; Zhu, Zhe; Obara, Elisabeth Anne Adanma; Miller, Tyler E.; Song, Anne; Lai, Sisi; Hubert, Christopher G.; Jin, Xun; Huang, Zhi; Fang, Xiaoguang; Dixit, Deobrat; Tao, Weiwei; Zhai, Kui; Chen, Cong; Dong, Zhen; Zhang, Guoxin; Dombrowski, Stephen; Hamerlik, Petra; Mack, Stephen C.; Bao, Shideng; Rich, Jeremy

doi:10.1016/j.stem.2018.03.011

Cited by 212 publications

(197 citation statements)

References 73 publications

(93 reference statements)

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“…4,5 Understanding which factors promote stemness and treatment resistance of glioma cells is of intense interest in developing new therapies in glioma. A large number of studies over the past decade have established that there is considerable plasticity in glioblastoma cell phenotypes, [6][7][8][9][10][11] that stem cell characteristics can be acquired by non-stem-like cells, 8,9,[12][13][14][15] and that microenvironmental cues such as hypoxia, 16 extracellular matrix proteins, [17][18][19][20][21][22][23][24][25] or growth factors secreted by stromal cells [26][27][28] may be sufficient to induce tumor cell stemness and therapeutic resistance. The role of the microenvironment in regulating tumor stemness is further supported by the finding that stem-like tumor cells are enriched in specific tumor niches; in GBM, primarily the perivascular niche (PVN) and hypoxic compartments.…”

Section: Introductionmentioning

confidence: 99%

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

Berg

Marques²,

Pantazopoulou

et al. 2020

Preprint

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The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance; however, little is known about how the microenvironment responds to radiation. Here, we found that astrocytes, when pre-irradiated, increased stemness and survival of co-cultured glioma cells. Tumor-naïve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. We identified extracellular matrix derived from irradiated astrocytes as a major driver of this phenotype, and astrocyte-derived transglutaminase 2 (TGM2) as a promoter of glioma stemness and radioresistance. TGM2 inhibitors abrogated glioma stemness induced by irradiated astrocytes. TGM2 inhibition reduced survival of glioma cells in in vitro and ex vivo tumor models.These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard of care radiotherapy in glioma.

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Section: Introductionmentioning

confidence: 99%

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

Berg

Marques²,

Pantazopoulou

et al. 2020

Preprint

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“…We chose these receptors based on their important roles in GBM biology. EGFR is a major driver of malignancy (Thorne et al, 2016), while p75NTR facilitates cell infiltration and its ligand is implicated in GBM progression (Johnston et al, 2007;Wang et al, 2018). We found that both EGFR and p75NTR were co-segregated with the PMGFP ACD reporter ( Fig.…”

Section: Acd Co-enriches Egfr and P75ntr Which Promotes Self-renewalmentioning

confidence: 68%

“…The net fitness of the tumor cannot be determined solely by that of tumorigenic cells such as CSCs or the most proliferative cells in the tumor; a dynamic interaction among the different types of tumor cells and their interaction with stromal cells are also critical factors. Furthermore, reciprocal crosstalk between CSCs and more differentiated tumor cells may contribute to tumor growth (Silver and Lathia, 2018;Wang et al, 2018). In this context, ACD may contribute to overall tumor growth by generating heterogeneous populations of cells that form a mutually beneficial paracrine network involving BDNF, a p75NTR ligand.…”

Section: Discussion Of Key Findingsmentioning

confidence: 99%

Asymmetric Division Promotes Therapeutic Resistance in Glioblastoma Stem Cells

Hitomi

Chumakova

Silver

et al. 2019

Preprint

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Asymmetric cell division (ACD) enables the maintenance of a stem cell population while simultaneously generating differentiated progeny. Cancer stem cells (CSCs) undergo multiple modes of cell division during tumor expansion and in response to therapy, yet the functional consequences of these division modes remain to be determined. Using a fluorescent reporter for cell surface receptor distribution during mitosis, we found that ACD in glioblastoma CSCs generated a daughter cell with enhanced therapeutic resistance and increased co-inheritance of epidermal growth factor receptor (EGFR) and neurotrophin receptor (p75NTR). Stimulation of both receptors maintained self-renewal under differentiation conditions. While p75NTR knockdown did not compromise CSC maintenance, therapeutic efficacy of EGFR inhibition was enhanced, indicating that co-inheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. These data demonstrate that ACD produces progeny with co-enriched growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population.

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“…Serum (FBS) is a variable and as yet undefined media supplement that contains many different soluble factors such as growth factors, hormones and vitamins, with potential to contribute to cell growth and survival (Brunner et al, ). Since the discovery that SF conditions more faithfully retained the original phenotype of GBM cells in culture, serum has often been used experimentally to demonstrate the differentiation potential and loss of GSC characteristics of SF established GSC cultures (Lee et al, ; Singh et al, ; Wang et al, ). The fact that ESCs could be maintained under serum conditions is not unexpected since this for decades was the standard GBM cell culture method, and the majority of our SFCs also had a maintainable sister SC.…”

Section: Discussionmentioning

confidence: 99%

A molecularly distinct subset of glioblastoma requires serum‐containing media to establish sustainable bona fide glioblastoma stem cell cultures

Maturi

Tan

Xie

et al. 2019

Glia

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Glioblastoma (GBM) is the most frequent and deadly primary malignant brain tumor. Hallmarks are extensive intra‐tumor and inter‐tumor heterogeneity and highly invasive growth, which provide great challenges for treatment. Efficient therapy is lacking and the majority of patients survive less than 1 year from diagnosis. GBM progression and recurrence is caused by treatment‐resistant glioblastoma stem cells (GSCs). GSC cultures are considered important models in target identification and drug screening studies. The current state‐of‐the‐art method, to isolate and maintain GSC cultures that faithfully mimic the primary tumor, is to use serum‐free (SF) media conditions developed for neural stem cells (NSCs). Here we have investigated the outcome of explanting 218 consecutively collected GBM patient samples under both SF and standard, serum‐containing media conditions. The frequency of maintainable SF cultures (SFCs) was most successful, but for a subgroup of GBM specimens, a viable culture could only be established in serum‐containing media, called exclusive serum culture (ESC). ESCs expressed nestin and SOX2, and displayed all functional characteristics of a GSC, that is, extended proliferation, sustained self‐renewal and orthotopic tumor initiation. Once adapted to the in vitro milieu they were also sustainable in SF media. Molecular analyses showed that ESCs formed a discrete group that was most related to the mesenchymal GBM subtype. This distinct subgroup of GBM that would have evaded modeling in SF conditions only provide unique cell models of GBM inter‐tumor heterogeneity.

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Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression

Cited by 212 publications

References 73 publications

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

Asymmetric Division Promotes Therapeutic Resistance in Glioblastoma Stem Cells

A molecularly distinct subset of glioblastoma requires serum‐containing media to establish sustainable bona fide glioblastoma stem cell cultures

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