Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5

Sun, Yongbing; Yan, Kun; Wang, Yi; Xu, Changwu; Wang, Dan; Zhou, Wei; Guo, Shuning; Han, Yahong; Tang, Lei; Shao, Yanqiu; Shan, Shaobo; Zhang, Qiangfeng Cliff; Tang, Yujie; Zhang, Liwei; Xi, Qiaoran

doi:10.1038/s43018-022-00408-8

Cited by 23 publications

(33 citation statements)

References 52 publications

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“…Very recently, it was shown in diffuse intrinsic pontine glioma, a very aggressive juvenile glioma type, that activation of BMP signalling enforces cellular differentiation similar to our findings presented in the current study. Mechanistically it was shown that upregulation of CHRDL1 expression results in counteraction of the tumor-suppressive effects of BMP4 and that depletion of CHRDL1 significantly reduced cell proliferation and sphere formation as well as tumor growth in a xenograft model [38]. The authors showed also, that BMP4 treatment of diffuse intrinsic pontine glioma (DIPG) cells induced a stemness-blockade accompanied by decreased SOX2 and OLIG2 expression further validating our findings.…”

Section: Discussionsupporting

confidence: 86%

“…The authors showed also, that BMP4 treatment of diffuse intrinsic pontine glioma (DIPG) cells induced a stemness-blockade accompanied by decreased SOX2 and OLIG2 expression further validating our findings. Mechanistically the authors proposed that by epigenetic upregulation of the tumor suppressor CXXC5 the BMP4-response is mediated [38]. Taken into account these studies, one may propose that (re-) activation of BMP4 signalling might be a suitable strategy to block the stem-like phenotype of adult and juvenile gliomas and thereby sensitizing them towards conventional therapy regimes.…”

Section: Discussionmentioning

confidence: 99%

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CHRDL1 Regulates Stemness in Glioma Stem-Like Cells

Berglar¹,

Hehlgans²,

Rödel³

et al. 2022

Preprint

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Glioblastoma (GBM) still presents as one of the most aggressive tumors in the brain, which despite enormous research efforts remains incurable until today. As many theories evolve around the persistent recurrence of this malignancy the assumption of a small population of cells with a stem-like phenotype remains as a key driver of its infiltrative nature. In this article we research Chordin-like 1 (CHRDL1), a secreted protein, as a potential key regulator of the glioma stem-like cell (GSC) phenotype. It has been shown that CHRDL1 antagonizes the function of Bone Morphogenic Protein 4 (BMP4), which induces GSC differentiation and hence reduces tumorigenicity. We therefore employed two previously described GSCs spheroid cultures and depleted them of CHRDL1 using stable transduction of a CHRDL1-targeting shRNA. We show with in vitro cell based assays (MTT, limiting dilution and sphere formation assays), western blots, irradiation procedures and quantitative real-time PCR that depletion of the secreted BMP4 antagonist CHRDL1 prominently decreases functional and molecular stemness traits resulting in enhanced radiation sensitivity. As a result, we postulate CHRDL1 as an enforcer of stemness in GSCs and find additional evidence that high CHRDL1-expression might also serve as a marker protein to determine BMP4-susceptibility.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

CHRDL1 Regulates Stemness in Glioma Stem-Like Cells

Berglar¹,

Hehlgans²,

Rödel³

et al. 2022

Preprint

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“…Interestingly, it has been proposed that IR treatment induces stemness in cancer cells [ 38 , 39 ] via the upregulation of SOX2 [ 38 ], among other known stemness factors. SOX2 is one of the major factors regulated by CHRDL1, as shown by us and others [ 40 ]. Therefore, it seems likely that CHRDL1 depletion not only counteracts this IR-induced stemness increase but even effectively prevents the stemness traits of GSCs.…”

Section: Discussionmentioning

confidence: 91%

“…Very recently, it was shown in diffuse intrinsic pontine glioma, a very aggressive juvenile glioma type, that the activation of BMP signalling enforces cellular differentiation, similar to our findings presented in the current study. Mechanistically it was shown that the upregulation of CHRDL1 expression results in the counteraction of the tumour-suppressive effects of BMP4 and that the depletion of CHRDL1 significantly reduces cell proliferation and sphere formation as well as tumour growth in a xenograft model [ 40 ]. The authors also showed that the BMP4 treatment of diffuse intrinsic pontine glioma (DIPG) cells induced a stemness blockade accompanied by decreased SOX2 and OLIG2 expression, further validating our findings.…”

Section: Discussionmentioning

confidence: 99%

“…The authors also showed that the BMP4 treatment of diffuse intrinsic pontine glioma (DIPG) cells induced a stemness blockade accompanied by decreased SOX2 and OLIG2 expression, further validating our findings. Mechanistically the authors proposed that by the epigenetic upregulation of the tumour suppressor CXXC5, the BMP4-response could be mediated [ 40 ]. Considering these studies, one may propose that the (re-) activation of BMP4 signalling might be a suitable strategy to block the stem-like phenotype of adult and juvenile gliomas and thereby sensitize them towards conventional therapy regimes.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CHRDL1 Regulates Stemness in Glioma Stem-like Cells

Berglar

Hehlgans

Wehle

et al. 2022

Cells

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Glioblastoma (GBM) still presents as one of the most aggressive tumours in the brain, which despite enormous research efforts, remains incurable today. As many theories evolve around the persistent recurrence of this malignancy, the assumption of a small population of cells with a stem-like phenotype remains a key driver of its infiltrative nature. In this article, we research Chordin-like 1 (CHRDL1), a secreted protein, as a potential key regulator of the glioma stem-like cell (GSC) phenotype. It has been shown that CHRDL1 antagonizes the function of bone morphogenic protein 4 (BMP4), which induces GSC differentiation and, hence, reduces tumorigenicity. We, therefore, employed two previously described GSCs spheroid cultures and depleted them of CHRDL1 using the stable transduction of a CHRDL1-targeting shRNA. We show with in vitro cell-based assays (MTT, limiting dilution, and sphere formation assays), Western blots, irradiation procedures, and quantitative real-time PCR that the depletion of the secreted BMP4 antagonist CHRDL1 prominently decreases functional and molecular stemness traits resulting in enhanced radiation sensitivity. As a result, we postulate CHRDL1 as an enforcer of stemness in GSCs and find additional evidence that high CHRDL1 expression might also serve as a marker protein to determine BMP4 susceptibility.

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Brain‐Targeted Exosomes‐Based Drug Delivery System to Overcome the Treatment Bottleneck of Brainstem Glioma

Chen

Shan

Xia

et al. 2023

Adv Funct Materials

Self Cite

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Brain health is the humans’ primary goal in achieving health and longevity. Brainstem glioma (BSG) has a high disability and mortality rate, posing a serious threat to children's brain health. Delivery of drugs to the brainstem is limited by poor tumor targeting and low blood‐brain barrier (BBB) permeability. Thus, it is a great challenge to construct intracranial drug delivery systems with strong biocompatibility, low immunogenicity, and high BBB permeability for the delivery of drugs targeting BSG. Exosomes, as the next generation of novel delivery systems, have been widely used to across the BBB due to their advantages of good biocompatibility, stability, and permeability of the BBB and have made corresponding breakthroughs in targeted drug delivery for CNS diseases. This review summarizes natural, polypeptide functionalized, and physical methods‐assisted brain‐targeted exosomes‐based drug delivery systems, the drug treatment bottleneck of BSG, and highlights the potential of using a brain‐targeted exosomes‐based drug delivery system to overcome the drug treatment bottleneck of BSG. It provides new insights into using exosomes‐based drug delivery for BSG treatment.

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Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5

Cited by 23 publications

References 52 publications

CHRDL1 Regulates Stemness in Glioma Stem-Like Cells

CHRDL1 Regulates Stemness in Glioma Stem-Like Cells

CHRDL1 Regulates Stemness in Glioma Stem-like Cells

Brain‐Targeted Exosomes‐Based Drug Delivery System to Overcome the Treatment Bottleneck of Brainstem Glioma

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