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Integrating Transcriptomics and 3D Spheroid Models Reveals Microenvironment-Dependent Purinergic Modulation in

Arieli Cruz de Sousa1,2,3, Augusto Ferreira Weber2,3, Vinícius Klain4

  • 1Laboratory of Differentiation, Proliferation, and Cell Viability, Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90610-264, RS, Brazil.

Metabolites
|March 27, 2026
PubMed
Summary

This study identifies a purinergic signaling signature linked to poor survival in hepatocellular carcinoma (HCC). Combined sorafenib and doxazosin therapy targets this pathway, overcoming resistance and increasing cancer cell death.

Keywords:
NT5Edoxazosindrug resistancehepatic stellate cellssorafenib

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Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Purinergic signaling, especially CD73, is dysregulated in hepatocellular carcinoma (HCC), impacting tumor growth, immune evasion, and chemoresistance.
  • Understanding the transcriptional landscape and tumor microenvironment's role is crucial for developing effective HCC therapies.

Purpose of the Study:

  • To characterize the transcriptional landscape of purinergic signaling in HCC.
  • To identify prognostic markers associated with purinergic system dysregulation.
  • To investigate the tumor microenvironment's influence on the response to combined sorafenib and doxazosin therapy in 3D spheroid models.

Main Methods:

  • RNA sequencing data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort.
  • Identification of differentially expressed genes, pathway enrichment, gene co-expression networks, and prognostic associations.
  • Machine learning for biomarker selection and assessment of drug targets in HepG2 and HepG2/LX-2 spheroids using qPCR and flow cytometry.

Main Results:

  • High expression of ADA, NT5E, and ADORA1 correlated with poor overall survival in HCC patients.
  • Combined sorafenib and doxazosin therapy downregulated NT5E and ADORA1 mRNA; ADORA2A was reduced in co-culture.
  • Combination therapy increased apoptosis (active caspase-3) in both mono- and co-culture spheroids, overcoming stromal protection.

Conclusions:

  • A purinergic prognostic signature for HCC was identified, with ADA, NT5E, and ADORA1 as key markers.
  • Sorafenib and doxazosin combination therapy effectively targets the adenosine pathway and specific receptors in HCC.
  • The stromal microenvironment maintains CD73 protein expression, emphasizing the importance of 3D co-culture models for studying therapeutic resistance.