Evidence map›Paper›PMID 34932815›Full record

ArticleNeuro-oncology2022

Neuronal exposure induces neurotransmitter signaling and synaptic mediators in tumors early in brain metastasis.

Krutika Deshpande, Vahan Martirosian, Brooke Naomi Nakamura, Mukund Iyer, Alex Julian, Rachel Eisenbarth, Ling Shao, Frank Attenello, Josh Neman

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

Article in Neuro-oncology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.

0numbers the graph read from it
0cells of the map it votes in
39citing papers in PubMed
2.2field-weighted citation impact, top 11% 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

39 citing papers in PubMed, 38 citations in OpenAlex.

  1. Trial
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  4. Molecular mechanisms and therapeutic targets in lung cancer-nerve crosstalk.Chinese medical journal pulmonary and critical care medicine · 2026
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  6. Article
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  18. Cancer Neuroscience: Decoding Neural Circuitry in Tumor Evolution for Targeted Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Review
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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

9 authors at 1 institution in 1 country.

Krutika DeshpandeDepartment of Neurological Surgery, University of Southern California, Los Angeles, California, USA.ORCID 0000-0003-3436-1413
Vahan MartirosianDepartment of Neurological Surgery, University of Southern California, Los Angeles, California, USA.
Brooke Naomi NakamuraDepartment of Medicine, Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, California, USA.
Mukund IyerDepartment of Neurological Surgery, University of Southern California, Los Angeles, California, USA.
Alex JulianDepartment of Neurological Surgery, University of Southern California, Los Angeles, California, USA.
Rachel EisenbarthDepartment of Neurological Surgery, University of Southern California, Los Angeles, California, USA.
Ling ShaoDepartment of Medicine, Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, California, USA.
Frank AttenelloDepartment of Neurological Surgery, University of Southern California, Los Angeles, California, USA.
Josh NemanDepartment of Neurological Surgery, University of Southern California, Los Angeles, California, USA.
University of Southern California · US

Funding

DOCTORAL AND POST-DOCTORAL TRAINING IN CRANIOFACIAL BIOLOGYT90DE021982 · NIDCR · UNIVERSITY OF SOUTHERN CALIFORNIA · PI PAINE, MICHAEL LANSDELL · 2011 to 2025
$6.2M
Microenvironmental contribution of the Choroid Plexus and Cerebral Spinal Fluid in breast to brain metastasesR01CA223544 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI NEMAN-EBRAHIM, JOSH · 2019 to 2023
$2.3M
NCI NIH HHS R01 CA223544NIDCR NIH HHS T90 DE021982
6 · The paper itself

Abstract

backgroundBrain metastases (BM) are responsible for neurological decline and poor overall survival. Although the pro-metastatic roles of glial cells, and the acquisition of neuronal attributes in established BM tumors have been described, there are no studies that investigate the initial interplay between neurons and brain-seeking tumor cells. The aim of this study was to characterize early tumor-neuron interactions and the induced CNS-adaptive changes in tumor cells prior to macro-colonization.

methodsUtilizing pure neuronal cultures and brain-naïve and patient-derived BM tumor cells, we surveyed the early induction of mediators of neurotransmitter (NT) and synaptic signaling in breast and lung tumor cells. Reliance on microenvironmental GABA in breast-to-brain metastatic cells (BBMs) was assessed in vitro and in vivo.

resultsCoculture with neurons induces early expression of classical NT receptor genes (HTR4, GRIA2, GRIN2B, GRM4, GRM8, DRD1) and neuronal synaptic mediators (CNR1, EGR2, ARC, NGFR, NRXN1) in breast and lung cancer cells. NT-dependent classification of tumor cells within the neuronal niche shows breast cancer cells become GABAergic responsive brain metastases (GRBMs) and transition from relying on autocrine GABA, to paracrine GABA from adjacent neurons; while autocrine Dopaminergic breast and lung tumor cells persist. In vivo studies confirm reliance on paracrine GABA is an early CNS-acclimation strategy in breast cancer. Moreover, neuronal contact induces early resurgence in Reelin expression in tumor cells through epigenetic activation, facilitating CNS adaptation.

conclusionTumor-neuron interactions allow for CNS adaptation early in the course of brain metastasis.

Indexed as

Brain NeoplasmsBreast NeoplasmsLung NeoplasmsFemalegamma-Aminobutyric AcidHumansNeuronsNeurotransmitter Agentsgamma-Aminobutyric AcidNeurotransmitter Agentsbrain metastasisneuronsneurotransmittersynaptic mediatorstumors

Identifiers

PMID34932815
PMCPMC9159425
OpenAlexW4200389940

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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.