BSTM-04. NEURONAL-ACTIVITY SECRETED BDNF INCREASES DIPG PROLIFERATION. Article Swipe

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Kathryn Taylor , Razina Aziz‐Bose , Ariane Blank , Anna C. Geraghty , Michelle Monje ·

YOU? · · 2019 · Open Access · · DOI: https://doi.org/10.1093/neuonc/noz036.021

Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that critically require novel therapeutic options. We have previously demonstrated that pHGG hijacks mechanisms of brain development and plasticity to their advantage. One key process, neuronal activity, robustly drives proliferation of pHGG via the secretion of the synaptic protein neuroligin-3 (NLGN3) and the neurotrophin brain-derived neurotrophic factor (BDNF) into the tumor microenvironment. Diffuse intrinsic pontine gliomas (DIPG) exhibit copy-number gain of neurotrophin receptor genes in a substantial fraction of cases (71/239, 29% cases with NTRK1, NTRK2 or NTRK3 gain/amplification), and primary DIPG tumor RNA-Seq confirms expression of the canonical BDNF receptor TrkB. Here, we investigated the role of microenvironmental BDNF on DIPG, independent of the NTRK fusion events commonly identified in infant HGG. We found spatio-temporal patterns of BDNF expression in normal brain during the postnatal developmental period that highlight this growth factor as particularly relevant to childhood gliomas. Conditioned media (CM) collected from optogenetically stimulated acute cortical slices robustly increases patient-derived DIPG cell proliferation, an effect that is abrogated with CM collected from mice deficient of activity-regulated BDNF expression. The BDNF ligand increases patient-derived DIPG cell proliferation and activates the canonical downstream MAPK signaling pathway. CRISPR deletion of the TrkB receptor, NTRK2, in DIPG cells abrogates the proliferative response to BDNF ligand exposure and subsequent p42/44 MAPK pathway activation. We are currently testing the in vivo growth potential of TrkB-deficient DIPG xenografts and the therapeutic potential of pharmacological TrkB antagonists. Disrupting DIPG responses to microenvironmental cues may highlight tumor dependencies and elucidate effective combinatorial therapeutic strategies. Funding: Abbie’s Army Foundation

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Brain-Derived Neurotrophic Factor

Concepts

Tropomyosin receptor kinase B Neurotrophic factors Brain-derived neurotrophic factor MAPK/ERK pathway Neurotrophin Biology Trk receptor Cancer research Neuroscience Receptor Internal medicine Cell biology Signal transduction Medicine Genetics

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Type: article
Language: en
Landing Page: https://doi.org/10.1093/neuonc/noz036.021
PDF: https://academic.oup.com/neuro-oncology/article-pdf/21/Supplement_2/ii67/28443372/noz036.021.pdf
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OpenAlex ID: https://openalex.org/W2941450039

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DOI: https://doi.org/10.1093/neuonc/noz036.021

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Title: BSTM-04. NEURONAL-ACTIVITY SECRETED BDNF INCREASES DIPG PROLIFERATION.

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Type: article

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Language: en

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Publication year: 2019

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Publication date: 2019-04-01

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Authors: Kathryn Taylor, Razina Aziz‐Bose, Ariane Blank, Anna C. Geraghty, Michelle Monje

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Landing page: https://doi.org/10.1093/neuonc/noz036.021

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Concepts: Tropomyosin receptor kinase B, Neurotrophic factors, Brain-derived neurotrophic factor, MAPK/ERK pathway, Neurotrophin, Biology, Trk receptor, Cancer research, Neuroscience, Receptor, Internal medicine, Cell biology, Signal transduction, Medicine, Genetics

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abstract_inverted_index.MAPK	193, 217
abstract_inverted_index.NTRK	115
abstract_inverted_index.TrkB	200, 239
abstract_inverted_index.cell	163, 186
abstract_inverted_index.cues	246
abstract_inverted_index.from	153, 173
abstract_inverted_index.gain	69
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abstract_inverted_index.into	58
abstract_inverted_index.mice	174
abstract_inverted_index.pHGG	21, 41
abstract_inverted_index.role	106
abstract_inverted_index.that	10, 20, 138, 167
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abstract_inverted_index.vivo	226
abstract_inverted_index.with	83, 170
abstract_inverted_index.DIPG,	111
abstract_inverted_index.Here,	102
abstract_inverted_index.NTRK2	85
abstract_inverted_index.NTRK3	87
abstract_inverted_index.TrkB.	101
abstract_inverted_index.acute	156
abstract_inverted_index.brain	25, 132
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abstract_inverted_index.media	150
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abstract_inverted_index.their	30
abstract_inverted_index.tumor	60, 92, 249
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abstract_inverted_index.(DIPG)	66
abstract_inverted_index.(pHGG)	3
abstract_inverted_index.CRISPR	196
abstract_inverted_index.NTRK1,	84
abstract_inverted_index.NTRK2,	202
abstract_inverted_index.drives	38
abstract_inverted_index.during	133
abstract_inverted_index.effect	166
abstract_inverted_index.events	117
abstract_inverted_index.factor	56, 142
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abstract_inverted_index.normal	131
abstract_inverted_index.p42/44	216
abstract_inverted_index.period	137
abstract_inverted_index.slices	158
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abstract_inverted_index.Diffuse	62
abstract_inverted_index.RNA-Seq	93
abstract_inverted_index.exhibit	67
abstract_inverted_index.gliomas	2, 65
abstract_inverted_index.hijacks	22
abstract_inverted_index.pathway	218
abstract_inverted_index.pontine	64
abstract_inverted_index.primary	90
abstract_inverted_index.protein	48
abstract_inverted_index.require	12
abstract_inverted_index.testing	223
abstract_inverted_index.(71/239,	80
abstract_inverted_index.Funding:	257
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abstract_inverted_index.confirms	94
abstract_inverted_index.cortical	157
abstract_inverted_index.deletion	197
abstract_inverted_index.diseases	9
abstract_inverted_index.exposure	213
abstract_inverted_index.fraction	77
abstract_inverted_index.gliomas.	148
abstract_inverted_index.neuronal	35
abstract_inverted_index.options.	15
abstract_inverted_index.pathway.	195
abstract_inverted_index.patterns	126
abstract_inverted_index.process,	34
abstract_inverted_index.receptor	72, 100
abstract_inverted_index.relevant	145
abstract_inverted_index.response	209
abstract_inverted_index.robustly	37, 159
abstract_inverted_index.synaptic	47
abstract_inverted_index.Abbie’s	258
abstract_inverted_index.Pediatric	0
abstract_inverted_index.abrogated	169
abstract_inverted_index.abrogates	206
abstract_inverted_index.activates	189
abstract_inverted_index.activity,	36
abstract_inverted_index.canonical	98, 191
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abstract_inverted_index.currently	222
abstract_inverted_index.deficient	175
abstract_inverted_index.effective	253
abstract_inverted_index.elucidate	252
abstract_inverted_index.highlight	139, 248
abstract_inverted_index.increases	160, 183
abstract_inverted_index.intrinsic	63
abstract_inverted_index.postnatal	135
abstract_inverted_index.potential	228, 236
abstract_inverted_index.receptor,	201
abstract_inverted_index.responses	243
abstract_inverted_index.secretion	44
abstract_inverted_index.signaling	194
abstract_inverted_index.Disrupting	241
abstract_inverted_index.Foundation	260
abstract_inverted_index.advantage.	31
abstract_inverted_index.critically	11
abstract_inverted_index.downstream	192
abstract_inverted_index.expression	95, 129
abstract_inverted_index.high-grade	1
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abstract_inverted_index.mechanisms	23
abstract_inverted_index.plasticity	28
abstract_inverted_index.previously	18
abstract_inverted_index.stimulated	155
abstract_inverted_index.subsequent	215
abstract_inverted_index.xenografts	232
abstract_inverted_index.Conditioned	149
abstract_inverted_index.activation.	219
abstract_inverted_index.copy-number	68
abstract_inverted_index.devastating	6
abstract_inverted_index.development	26
abstract_inverted_index.expression.	179
abstract_inverted_index.independent	112
abstract_inverted_index.strategies.	256
abstract_inverted_index.substantial	76
abstract_inverted_index.therapeutic	14, 235, 255
abstract_inverted_index.antagonists.	240
abstract_inverted_index.demonstrated	19
abstract_inverted_index.dependencies	250
abstract_inverted_index.investigated	104
abstract_inverted_index.neuroligin-3	49
abstract_inverted_index.neurotrophic	55
abstract_inverted_index.neurotrophin	53, 71
abstract_inverted_index.particularly	144
abstract_inverted_index.brain-derived	54
abstract_inverted_index.combinatorial	254
abstract_inverted_index.developmental	136
abstract_inverted_index.proliferation	39, 187
abstract_inverted_index.proliferative	208
abstract_inverted_index.TrkB-deficient	230
abstract_inverted_index.proliferation,	164
abstract_inverted_index.optogenetically	154
abstract_inverted_index.patient-derived	161, 184
abstract_inverted_index.pharmacological	238
abstract_inverted_index.spatio-temporal	125
abstract_inverted_index.microenvironment.	61
abstract_inverted_index.activity-regulated	177
abstract_inverted_index.microenvironmental	108, 245
abstract_inverted_index.gain/amplification),	88
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cited_by_percentile_year.min	89
countries_distinct_count	1
institutions_distinct_count	5
sustainable_development_goals[0].id	https://metadata.un.org/sdg/2
sustainable_development_goals[0].score	0.5400000214576721
sustainable_development_goals[0].display_name	Zero hunger
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citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False