Evidence map›Paper›PMID 34879849›Full record

ArticleBMC cancer2021

Transcription factor network analysis based on single cell RNA-seq identifies that Trichostatin-a reverses docetaxel resistance in prostate Cancer.

Patricia M Schnepp, Aqila Ahmed, June Escara-Wilke, Jinlu Dai, Greg Shelley, Jill Keller, Atsushi Mizokami, Evan T Keller

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in BMC cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
0.8field-weighted citation impact, top 33% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 11 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 2 institutions in 2 countries.

Patricia M SchneppDepartment of Urology, University of Michigan Medical School, NCRC B14 RM116, Ann Arbor, MI, 48109, USA.
Aqila AhmedDepartment of Urology, University of Michigan Medical School, NCRC B14 RM116, Ann Arbor, MI, 48109, USA.
June Escara-WilkeDepartment of Urology, University of Michigan Medical School, NCRC B14 RM116, Ann Arbor, MI, 48109, USA.
Jinlu DaiDepartment of Urology, University of Michigan Medical School, NCRC B14 RM116, Ann Arbor, MI, 48109, USA.
Greg ShelleyDepartment of Urology, University of Michigan Medical School, NCRC B14 RM116, Ann Arbor, MI, 48109, USA.
Jill KellerDepartment of Urology, University of Michigan Medical School, NCRC B14 RM116, Ann Arbor, MI, 48109, USA.
Atsushi MizokamiDepartment of Urology, Kanazawa University, Kanazawa, Japan.
Evan T KellerDepartment of Urology, University of Michigan Medical School, NCRC B14 RM116, Ann Arbor, MI, 48109, USA. etkeller@med.umich.edu.
University of Michigan–Ann Arbor · USKanazawa University · JP

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundOvercoming drug resistance is critical for increasing the survival rate of prostate cancer (PCa). Docetaxel is the first cytotoxic chemotherapeutical approved for treatment of PCa. However, 99% of PCa patients will develop resistance to docetaxel within 3 years. Understanding how resistance arises is important to increasing PCa survival.

methodsIn this study, we modeled docetaxel resistance using two PCa cell lines: DU145 and PC3. Using the Passing Attributes between Networks for Data Assimilation (PANDA) method to model transcription factor (TF) activity networks in both sensitive and resistant variants of the two cell lines. We identified edges and nodes shared by both PCa cell lines that composed a shared TF network that modeled changes which occur during acquisition of docetaxel resistance in PCa. We subjected the shared TF network to connectivity map analysis (CMAP) to identify potential drugs that could disrupt the resistant networks. We validated the candidate drug in combination with docetaxel to treat docetaxel-resistant PCa in both in vitro and in vivo models.

resultsIn the final shared TF network, 10 TF nodes were identified as the main nodes for the development of docetaxel resistance. CMAP analysis of the shared TF network identified trichostatin A (TSA) as a candidate adjuvant to reverse docetaxel resistance. In cell lines, the addition of TSA to docetaxel enhanced cytotoxicity of docetaxel resistant PCa cells with an associated reduction of the IC50 of docetaxel on the resistant cells. In the PCa mouse model, combination of TSA and docetaxel reduced tumor growth and final weight greater than either drug alone or vehicle.

conclusionsWe identified a shared TF activity network that drives docetaxel resistance in PCa. We also demonstrated a novel combination therapy to overcome this resistance. This study highlights the usage of novel application of single cell RNA-sequencing and subsequent network analyses that can reveal novel insights which have the potential to improve clinical outcomes.

Indexed as

Prostatic NeoplasmsTranscription FactorsAnimalsAntineoplastic AgentsCell Line, TumorDocetaxelDrug Resistance, NeoplasmHumansHydroxamic AcidsMaleMiceProtein Interaction MapsRNA-SeqSingle-Cell AnalysisAntineoplastic AgentsDocetaxelHydroxamic AcidsTranscription Factorstrichostatin ADocetaxel resistance prostate cancerPANDA methodSingle cell RNA sequencingTranscription factor network analysisTrichostatin a

Identifiers

PMID34879849
PMCPMC8653542
OpenAlexW4200441563

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.