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Intercellular crosstalk shapes purinergic metabolism and signaling in cancer cells

Julia Hesse1, Bodo Steckel2, Peter Dieterich3

  • 1Department of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany; CARID, Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

Cell Reports
|January 4, 2024
PubMed

Insights

Adenosine metabolism varies by cancer type, influenced by ecto-adenosine deaminase (ADA) activity. This purine metabolism heterogeneity impacts anti-cancer immunity and may affect CD73 inhibitor efficacy.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Immunology

Background:

  • CD73 generates adenosine, suppressing anti-cancer immunity.
  • CD73 inhibitors are under clinical investigation for cancer therapy.

Purpose of the Study:

  • To investigate purine ectoenzyme kinetics across diverse cancer cell lines.
  • To understand how hypoxia and cancer type influence adenosine metabolism.
  • To correlate purine metabolism with immune cell interactions in the tumor microenvironment.

Main Methods:

  • Assessed enzyme kinetics of purinergic ectoenzymes in five cancer cell lines (Hodgkin lymphoma, multiple myeloma, pancreas adenocarcinoma, urinary bladder carcinoma, glioblastoma) under normoxia and hypoxia.
  • Combined enzyme kinetics data with single-cell RNA sequencing data from myeloma and glioblastoma tissues.
  • Analyzed purine metabolism heterogeneity across malignant, stromal, and immune cells.

Main Results:

  • Significant variation in adenosine metabolism was observed among different cancer types.
  • High ecto-adenosine deaminase (ADA) activity was prevalent across all tested cell lines, impacting adenosine accumulation kinetics.
  • Purine metabolism exhibited cancer type-specific spatial heterogeneity within the tumor microenvironment, differing between malignant, stromal, and immune cells.

Conclusions:

  • Adenosine metabolism is highly variable and cancer type-specific.
  • Ecto-adenosine deaminase (ADA) activity and spatial heterogeneity are critical factors influencing bioactive adenosine levels in the tumor microenvironment.
  • These findings have implications for the efficacy of CD73-targeted cancer immunotherapies.
Keywords:
CP: CancerNADadenosineadenosine deaminaseglioblastomahypoxiamultiple myeloma

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